Pyridones useful as inhibitors of kinases

ABSTRACT

The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing the compounds of the invention and intermediate compounds useful in these processes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/673,870, filed Apr. 22, 2005 and U.S. Provisional Application60/636,754, filed Dec. 16, 2004, which are incorporated herein in theirentirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofprotein kinases. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders. Theinvention also provides processes for preparing the compounds of theinvention and intermediate compounds useful in these processes.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. (See, Hardie, G. and Hanks, S.The Protein Kinase Facts Book, I and II, Academic Press, San Diego,Calif.: 1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these kinase families(See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596;Knighton et al., Science 1991, 253, 407-414; Hiles et al., Cell 1992,70, 419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al.,EMBO J. 1994, 13, 2352-2361).

In general, protein kinases mediate intracellular signaling by effectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxin, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1)and tumor necrosis factor α (TNF-α)), and growth factors (e.g.,granulocyte macrophage-colony-stimulating factor (GM-CSF), andfibroblast growth factor (FGF)). An extracellular stimulus may affectone or more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events as described above. These diseasesinclude, but are not limited to, autoimmune diseases, inflammatorydiseases, bone diseases, metabolic diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease, and hormone-related diseases.Accordingly, there has been a substantial effort in medicinal chemistryto find protein kinase inhibitors that are effective as therapeuticagents.

The Tec family of non-receptor tyrosine kinases plays a central role insignaling through antigen-receptors such as the TCR, BCR and Fcereceptors (reviewed in Miller A, et al., Current Opinion in Immunology14; 331-340 (2002). Tec family kinases are essential for T cellactivation. Three members of the Tec family, Itk, Rlk and Tec, areactivated downstream of antigen receptor engagement in T cells andtransmit signals to downstream effectors, including PLC-γ. Deletion ofItk in mice results in reduced T cell receptor (TCR)-inducedproliferation and secretion of the cytokines IL-2, IL-4, IL-5, IL-10 andIFN-γ (Schaeffer et al, Science 284; 638-641 (1999)), Fowell et al,Immunity 11; 399-409 (1999), Schaeffer et al Nature Immunology 2, 12;1183-1188 (2001))). The immunological symptoms of allergic asthma areattenuated in Itk−/− mice. Lung inflammation, eosinophil infiltrationand mucous production are drastically reduced in Itk−/− mice in responseto challenge with the allergen OVA (Mueller et al, Journal of Immunology170: 5056-5063 (2003)). Itk has also been implicated in atopicdermatitis. This gene has been reported to be more highly expressed inperipheral blood T cells from patients with moderate and/or severeatopic dermatitis than in controls or patients with mild atopicdermatitis (Matsumoto et al, International archives of Allergy andImmunology 129; 327-340 (2002)).

Splenocytes from Rlk−/− mice secrete half the IL-2 produced by wild typeanimals in response to TCR engagement (Schaeffer et al, Science 284;638-641 (1999)), while combined deletion of Itk and Rlk in mice leads toa profound inhibition of TCR-induced responses including proliferationand production of the cytokines IL-2, IL-4, IL-5 and IFN-γ (Schaeffer etal Nature Immunology 2, 12; 1183-1188 (2001)), Schaeffer et al, Science284; 638-641 (1999)). Intracellular signaling following TCR engagementis effected in Itk/Rlk deficient T cells; inositol triphosphateproduction, calcium mobilization, MAP kinase activation, and activationof the transcription factors NFAT and AP-1 are all reduced (Schaeffer etal, Science 284; 638-641 (1999), Schaeffer et al Nature Immunology 2,12; 1183-1188 (2001)).

Tec family kinases are also essential for B cell development andactivation. Patients with mutations in Btk have a profound block in Bcell development, resulting in the almost complete absence of Blymphocytes and plasma cells, severely reduced Ig levels and a profoundinhibition of humoral response to recall antigens (reviewed in Vihinenet al Frontiers in Bioscience 5:d917-928). Mice deficient in Btk alsohave a reduced number of peripheral B cells and greatly decreased levelsof IgM and IgG3. Btk deletion in mice has a profound effect on B cellproliferation induced by anti-IgM, and inhibits immune responses tothymus-independent type II antigens (Ellmeier et al, J Exp Med192:1611-1623 (2000)).

Tec kinases also play a role in mast cell activation through thehigh-affinity IgE receptor (FcεRI). Itk and Btk are expressed in mastcells and are activated by FcεRI cross-linking (Kawakami et al, Journalof Immunology; 3556-3562 (1995)). Btk deficient murine mast cells havereduced degranulation and decreased production of proinflammatorycytokines following FcεRI cross-linking (Kawakami et al. Journal ofleukocyte biology 65:286-290). Btk deficiency also results in a decreaseof macrophage effector functions (Mukhopadhyay et al, Journal ofImmunology; 168, 2914-2921 (2002)).

Accordingly, there is a great need to develop compounds useful asinhibitors of protein kinases. In particular, it would be desirable todevelop compounds that are useful as inhibitors of Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases, particularly giventhe inadequate treatments currently available for the majority of thedisorders implicated in their activation.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of protein kinases. In certain embodiments, these compoundsare effective as inhibitors of Tec family (e.g., Tec, Btk, Itk/Emt/Tsk,Bmx, Txk/Rlk) protein kinases. These compounds have the formula I asdefined herein or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions thereof areuseful for treating or preventing a variety of diseases, disorders orconditions, including, but not limited to, an autoimmune, inflammatory,proliferative, or hyperproliferative disease or animmunologically-mediated disease. The compositions are also useful inmethods for preventing thrombin-induced platelet aggregation. Thecompounds provided by this invention are also useful for the study ofkinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such kinases; andthe comparative evaluation of new kinase inhibitors.

Also provided by this invention are processes for preparing compounds ofthis invention and intermediate compounds useful in these processes.

DETAILED DESCRIPTION OF THE INVENTION

This invention describes compounds of Formula I:

or a pharmaceutically accepted salt thereof, wherein

-   each R³ and R⁴ is independently H, halogen or C₁₋₄ aliphatic    optionally substituted with halogen, C₁₋₂aliphatic, OCH₃, NO₂, NH₂,    CN, NHCH₃, SCH₃, or N(CH)₂.-   R² is a 3-8-membered saturated, partially unsaturated, or fully    unsaturated monocyclic ring having 0-3 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or an 8-12 membered    saturated, partially unsaturated, or fully unsaturated bicyclic ring    system having 0-5 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; R² is optionally substituted with J^(R);    each X¹ and X² is independently —C(O)—, —NR—, or —SO₂— wherein one    of X¹ or X² is —NR— and the other of X¹ or X² is —C(O)— or —SO₂—;-   R is H, unsubstituted C₁₋₆ aliphatic;-   R¹ is -T-Q;-   T is a bond or C₁₋₆ aliphatic, wherein up to three methylene units    of the chain are optionally and independently replaced by G or G′    wherein G is —NR⁵—, —O—, —S—, —SO—, SO₂—, —CS—, or —CO—; G′ is    cyclopropyl, C≡C, or C═C; T is optionally substituted with J^(T);-   Q is independently hydrogen, a C₁₋₆ aliphatic group, a 3-8-membered    saturated, partially unsaturated, or fully unsaturated monocyclic    ring having 0-3 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or an 8-12 membered saturated, partially    unsaturated, or fully unsaturated bicyclic ring system having 0-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    Q is optionally substituted with J^(Q);-   R⁵ is optionally substituted R, C₆₋₁₀ aryl, C₃₋₁₀ cycloaliphatic,    5-14 membered heteroaryl, or 5-14 membered heterocyclyl; or two R⁵    groups, together with the atom(s) to which they are attached, form    an optionally substituted 3-7 membered monocyclic or 8-14 membered    bicyclic ring;    the optional substituents J^(R), J^(T), and J^(Q) are defined    herein.

Certain embodiments of this invention provide that

when R² is 4-pyridyl or 3-pyridyl, R³ is H, X¹ is —NR—, R is H, and X²is —C(O)—; then

-   -   a) R¹ is not CH(CH₃)OC(═O)CH₃; CH₂C(═O)CH₃; or CH₂C(═O)CH₃;    -   b) R¹ is not C₁₋₆alkyl or O(C₁₋₆alkyl);        when R² is 4-pyridyl, R³ and R⁴ are H, X¹ is —NR—, R is H, and        X² is —C(O)—, then    -   a) when T is a bond, Q is not methyl, imidazole, OCH₃, or H;    -   b) when T is —CH₂—, Q is not 3-OH-phenyl, 4-OH-phenyl,        4-pyridyl, 3-NO₂-phenyl, OH, —O(C═O)CH₃, or —C(═O)CH₃;    -   c) when T is —CH(CH₃)—, Q is not —OC(═O)CH₃;    -   d) when T is —CH₂CH₂—, Q is not 2-pyridyl or —COOH;    -   e) when T is CH(CH₃)OC(═O)—, Q is not CH₃;        when R² is 4-pyridyl, R³ is H, R⁴ is not H, X¹ is —NR—, R is H,        and X² is —C(O)—, then    -   a) when T is a bond, Q is not CH₃;    -   b) R¹ is not CH(CH₃)OC(═O)CH₃;        when R² is 2,4-pyrimidyl, R³ and R⁴ are H, X¹ is —NR—, R is H,        and X² is —C(O)—, then    -   a) R¹ is not methyl, NHCH₃, or —NHC(═O)NH₂;        when R² is 4-pyridyl, R³ and R⁴ are H, X¹ is —NR—, R is H, and        X² is —SO₂—, then    -   a) when T is a bond, Q is not optionally substituted C₆₋₁₀ aryl        or C₅₋₁₀ heteroaryl;        when R² is 4-thiazolyl, R³ is H, R⁴ is CH₃, X¹ is —C(O)—, X² is        —NR—, R is H, then    -   a) when T is —CH₂CH₂—, Q is not N(CH₃)₂;        when R² is unsubstituted phenyl, R³ and R⁴ are H, X¹ is —NR—, R        is H, and X² is —C(O)—, then, when T is C₁aliphatic wherein 1        methylene unit of the chain is replaced by G; G is —NR⁵—; and R⁵        is H; then Q is not 2,6-di-isopropylphenyl;        when R² is unsubstituted phenyl, R³ is H, R⁴ is CH₃, X¹ is        —C(O)—, X² is —NR—, R is H, then    -   a) when T is a bond, Q is not CH₃ or CH₂CH₃;    -   b) when T is —CH₂CH₂—, Q is not unsubstituted phenyl or        N(CH₂CH₃)₂;    -   c) when T is —CH₂CH₂CH₂—, Q is not N(CH₂CH₃)₂;    -   d) R¹ is not NH₂;        when R² is unsubstituted phenyl, R³ is H, R⁴ is CH₃, X¹ is —NR—,        R is H, X² is —C(O)—, then    -   a) when T is —O—CH₂—, Q is not unsubstituted phenyl;        when R² is 4-OCH₃ phenyl, R³ is H, R⁴ is CH₃, X¹ is —NR—, R is        H, X² is —C(O)—, then    -   a) when T is a bond, Q is not CH₃;        when R² is a 6-membered heteroaryl with 2 nitrogens; R³ is H,        methyl, or ethyl; R⁴ is methyl or ethyl; X¹ is —NR—, R is H, X²        is —C(O)—, then    -   a) R¹ is not CH₃;        when X¹ is —C(O)—, X² is —NR—, and R is H, then R¹ is not H or        methyl;        when R² is        R³ and R⁴ are H, X¹ is —NR—, R is H, and X² is —C(O)—, then R¹        is not CH₃;        when R² is unsubstituted phenyl, R³ and R⁴ are H, X¹ is —C(O)—,        X² is —NR—, R is H, then

-   R¹ is not

Other embodiments of this invention provide thatwhen R² is 4-pyridyl, 3-pyridyl, or

R³ is H, X¹ is —NR—, R is H, and X² is —C(O)—; then

-   -   a) R¹ is not H, C₁₋₆alkyl, O(C₁₋₆alkyl), CH(CH₃)OC(═O)CH₃, or        imidazole;    -   b) when T is —CH₂—, Q is not 3-OH-phenyl, 4-OH-phenyl,        4-pyridyl, 3-NO₂-phenyl, OH, OC(═O)CH₃, or —C(═O)CH₃;    -   c) when T is —CH₂CH₂—, Q is not 2-pyridyl or —COOH;        when R² is 2,4-pyrimidyl, R³ and R⁴ are H, X¹ is —NR—, R is H,        and X² is —C(O)—, then    -   a) R¹ is not methyl, NHCH₃, or —NHC(═O)NH₂;        when R² is 4-pyridyl, R³ and R⁴ are H, X¹ is —NR—, R is H, and        X² is —SO₂—, then    -   a) when T is a bond, Q is not optionally substituted C₆₋₁₀ aryl        or C₅₋₁₀ heteroaryl;        when R² is 4-thiazolyl, R³ is H, R⁴ is CH₃, X¹ is —C(O)—, X² is        —NR—, R is H, then    -   a) when T is —CH₂CH₂—, Q is not N(CH₃)₂;        when R² is optionally substituted phenyl, R³ is H, X¹ is —NR—, R        is H, and X² is —C(O)—, then,    -   a) when T is C₁aliphatic wherein 1 methylene unit of the chain        is replaced by G; G is —NR⁵—; and R⁵ is H; then Q is not        2,6-di-isopropylphenyl;    -   b) when T is —O—CH₂—, Q is not unsubstituted phenyl;    -   c) when T is a bond, Q is not CH₃;        when R² is unsubstituted phenyl, R³ is H, X¹ is —C(O)—, X² is        —NR—, R is H, then    -   a) when T is a bond, Q is not CH₃ or CH₂CH₃;    -   b) when T is —CH₂CH₂—, Q is not unsubstituted phenyl or        N(CH₂CH₃)₂;    -   c) when T is —CH₂CH₂CH₂—, Q is not N(CH₂CH₃)₂;    -   d) R¹ is not NH₂ or        when R² is a 6-membered heteroaryl with 2 nitrogens; R³ is H,        methyl, or ethyl; R⁴ is methyl or ethyl; X¹ is —NR—, R is H, X²        is —C(O)—, then R¹ is not CH₃;        when X¹ is —C(O)—, X² is —NR—, and R is H, then R¹ is not H or        methyl.

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “optionally interrupted” refers to the replacement of one atomwithin an alkylidene chain with another atom. Unless otherwisespecified, the second atom can replace the first atom at any position,including terminal atoms. For example, a C₁₋₃ alkyl chain optionallyinterrupted with —O— can form —OCH₂CH₃, —CH₂—OCH₃, or CH₂CH₂OH. Unlessotherwise specified, the terminal groups are bonded to hydrogen on theterminal side.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3-7 members. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

It should be understood that ring systems herein may be linearly fused,bridged, or spirocyclic.

The term “heteroaliphatic”, as used herein, means aliphatic groupswherein one or two carbon atoms are independently replaced by one ormore of oxygen, sulfur, nitrogen, phosphorus, or silicon.Heteroaliphatic groups may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and include “heterocycle”,“heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members are anindependently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Suitable substituents (e.gJ^(R), J^(T), and J^(Q)) on the unsaturated carbon atom of an aryl orheteroaryl group are selected from halogen; —R^(o); C₁₋₆alkyl,optionally substituted with R^(o), wherein up to three methylene unitsof the chain are optionally and independently replaced by, —NR^(o)—,—O—, —S—, —SO—, SO₂—, or —CO— in a chemically stable arrangement; —OCF₃;—SCF₂; C₁₋₄haloalkyl; —CH₂-halogen; C₆₋₁₀aryl, optionally substitutedwith R^(o); a 5-12 membered heteroaryl optionally substituted withR^(o); 3-12 membered heterocyclic ring optionally substituted withR^(o); —O(Ph) optionally substituted with R^(o); —CH═CH(Ph), optionallysubstituted with R^(o); —CH≡CH(Ph), optionally substituted with R^(o),—C₁₋₆alkyl-(5-12 membered heterocyclyl), optionally substituted withR^(o); —C₁₋₆alkyl-(C₆₋₁₀aryl), optionally substituted with R^(o),—C₁₋₆alkyl-(5-10 membered heteroaryl), optionally substituted withR^(o); C₃₋₁₀cycloaliphatic optionally substituted with R^(o);—C₁₋₆alkyl-(C₃₋₁₀cycloaliphatic), optionally substituted with R^(o);—(C₁₋₆alkyl)-OR^(o), optionally substituted with R^(o);—(C₁₋₆alkyl)-N(R^(o))₂, optionally substituted with R^(o);—(C₁₋₆alkyl)-SR^(o), optionally substituted with R^(o); —NO₂; —CN;—OR^(o); —SR^(o); —N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o);—NR^(o)C(O)N(R^(o))₂; —NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o);—NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o)C(O)N(R^(o))₂;—NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o);—C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂; —OC(O)N(R^(o))₂;—OC(O)R^(o); —C(O)N(OR^(o))R^(o); —C(NOR^(o))R^(o); —S(O)₂R^(o);—S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o); —NR^(o)SO₂N(R^(o))₂;—NR^(o)SO₂R^(o); —N(OR^(o))R^(o); —C(═NH)—N(R^(o))₂; —P(O)₂R^(o);—PO(R^(o))₂; —OPO(R^(o))₂; and —(CH₂)₀₋₂NHC(O)R^(o);

Each R^(o) is independently selected from hydrogen, NH₂,NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, OH, O(C₁₋₄aliphatic),NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic),haloC₁₋₄aliphatic, optionally substituted C₁₋₆ aliphatic wherein up to 2methylene units are optionally replaced by O, N, or S, optionallysubstituted 5-8 membered heterocyclyl, unsubstituted 5-6 memberedheteroaryl, unsubstituted 3-6 membered cycloaliphatic, unsubstitutedphenyl, unsubstituted —O(Ph), unsubstituted —CH₂(Ph), unsubstituted—CH₂(5-7 membered heterocyclyl), or unsubstituted —CH₂(5-6 memberedheteroaryl); or, notwithstanding the definition above, two independentoccurrences of R^(o), on the same substituent or different substituents,taken together with the atom(s) to which each R^(o) group is bound, forman optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Optional substituents on the aliphatic group of R^(o) or on the ringformed by 2 R^(o) groups are selected from NH₂, NH(C₁₋₄aliphatic),N(C₁₋₄aliphatic)₂, halogen, C₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN,CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), and haloC₁₋₄aliphatic,wherein each of the foregoing C₁₋₄aliphatic groups of R^(o) isunsubstituted;

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents. Suitable substituents (e.gJ^(R), J^(T), and J^(Q)) on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic heterocyclic ring areselected from those listed above for the unsaturated carbon of an arylor heteroaryl group and additionally include the following: ═O, ═S,═NNHR*, ═NN(R*)₂, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), ═NOH, and═NR*, where each R* is independently selected from hydrogen and anoptionally substituted C₁₋₆ aliphatic. Optional substituents on thealiphatic group of R* are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN,CO₂H, CO₂(C₁₋₄ aliphatic), O(halo C₁₋₄ aliphatic), and halo(C₁₋₄aliphatic), wherein each of the foregoing C₁₋₄aliphatic groups of R* isunsubstituted.

Optional substituents (e.g J^(R), J^(T), and J^(Q)) on the nitrogen of anon-aromatic heterocyclic ring or on the nitrogen of the heteroaryl ringare selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, and—NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆aliphatic, optionally substituted phenyl, optionally substituted —O(Ph),optionally substituted —CH₂(Ph), optionally substituted —(CH₂)₂(Ph);optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 memberedheteroaryl or heterocyclic ring having one to four heteroatomsindependently selected from oxygen, nitrogen, and sulfur, or,notwithstanding the definition above, two independent occurrences of R⁺,on the same substituent or different substituents, taken together withthe atom(s) to which each R⁺ group is bound, form a 5-8-memberedheterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloaliphaticring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Optional substituents on the aliphatic group or thephenyl ring of R⁺ are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN,CO₂H, CO₂(C₁₋₄ aliphatic), O(halo C₁₋₄ aliphatic), and halo(C₁₋₄aliphatic), wherein each of the foregoing C₁₋₄aliphatic groups of R⁺ isunsubstituted.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule, wherein one or more methylene units may optionally andindependently be replaced with a group including, but not limited to,CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂,NRSO₂, SO₂NR, NRSO₂NR, O, S; or NR.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined herein), are takentogether with the atom(s) to which each variable is bound to form a5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-memberedcycloalkyl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Exemplary rings that are formed when twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) are taken together with the atom(s) to which eachvariable is bound include, but are not limited to the following: a) twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) that are bound to the same atom and are taken togetherwith that atom to form a ring, for example, N(R^(o))₂, where bothoccurrences of R^(o) are taken together with the nitrogen atom to form apiperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of OR^(o)

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

Unless otherwise stated, structures depicted herein are also meant toinclude an N-oxide derivative or a pharmaceutically acceptable salt ofeach of the compounds of formula I.

According to one embodiment of this invention, T is C₁₋₃aliphaticoptionally interrupted with zero or one G groups wherein G is selectedfrom O, NR⁵, and S.

In some embodiments, T is —C₁₋₂aliphatic-G- wherein G is O or NR⁵, and Gis bound to Q in a chemically stable arrangement. In other embodiments,G is bound to X² in a chemically stable arrangement. In yet otherembodiments T is C₁₋₃aliphatic optionally interrupted with zero Ggroups.

In some embodiments, T is C₁₋₃aliphatic optionally interrupted with zeroor one G′ groups. In other embodiments, T is C₁₋₃aliphatic optionallyinterrupted with zero or one G or G′ groups.

In some embodiments, T is —CH₂—; in other embodiments T is a bond.

According to one embodiment of the invention, each R³ and R⁴ isindependently H. In some embodiments, both R³ and R⁴ are H.

According to some embodiments R² is a 5-8 membered monocyclyl optionallysubstituted with up to 5 J^(R) groups. In certain embodiments, R² is a5-6 membered aryl or heteroaryl optionally substituted with up to 5J^(R) groups. In other embodiments R² is a 5-6 membered heteroaryloptionally substituted with up to 5 J^(R) groups, preferably R² is a 6membered heteroaryl having 1 or 2 nitrogen atoms wherein R² isoptionally substituted with up to 5 J^(R) groups.

In some embodiments, R² is C₃₋₈cycloaliphatic optionally substitutedwith up to five J^(R) groups. In other embodiments, R² is C₃₋₈cycloalkyloptionally substituted with up to five J^(R) groups. In certainembodiments, R² is C₃₋₈cycloalkenyl optionally substituted with up tofive J^(R) groups. In other embodiments, R² is cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, or cycloheptenyl,optionally substituted with up to five J^(R) groups.

In some embodiments R² is a pyridine ring optionally substituted with upto 5 J^(R) groups. In some embodiments, R² is 2-pyridinyl, 3-pyridyl, or4-pyridyl optionally substituted with up to five J^(R) groups. Incertain embodiments, R² is a pyrimidine ring optionally substituted withup to five J^(R) groups. In some embodiments, R² is a 2,4 pyrimidinyl.In other embodiments, R² is a 5-membered heteroaryl ring optionallysubstituted with up to five J^(R) groups. In some embodiments, R² isthiophene or pyrazole optionally substituted with up to five J^(R)groups. In yet other embodiments R is phenyl optionally substituted withup to 5 J^(R) groups.

In some embodiments R² is optionally substituted with up to 5 J^(R)groups; in other embodiments, up to 3 J^(R) groups; in yet otherembodiments, 0 or 1 J^(R) groups.

In some embodiments of this invention, J^(R) is selected from C₁₋₆alkyl,C₆₋₁₀aryl, —C₁₋₆alkyl-C₆₋₁₀aryl, C₁₋₄haloalkyl, —OR^(o), —N(R^(o))₂,—SR^(o), 3-12 membered heterocyclyl, —(C₁₋₆alkyl)-OR^(o),—(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), —C(O)OR^(o),—NR^(o)COR^(o), —COR^(o), —CON(R^(o))₂, —SO₂R^(o), —SO₂N(R^(o))₂, andC₁₋₆alkyl wherein up to three methylene units of the chain areindependently replaced by, —NR^(o)—, —O—, —S—, —SO—, SO₂—, or —CO— in achemically stable arrangement.

In certain embodiments, J^(R) is selected from oxo or ═NOH.

In other embodiments J^(R) is —OR^(o), —N(R^(o))₂, —SR^(o), NO₂, CN,—(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, or —(C₁₋₆alkyl)-SR^(o).

In some embodiments, each J^(R) is independently selected fromoptionally substituted 5-8 membered heterocyclyl, optionally substituted—NR(C₁₋₄alkyl)N(R^(o))₂, optionally substituted —NR(C₁₋₄alkyl)OR^(o),—N(R^(o))₂, or optionally substituted —NH(5-6 membered heterocyclyl). Incertain embodiments J^(R) is —NH(C₁₋₄alkyl)N(R^(o))₂; in otherembodiments —NH(C₁₋₄alkyl)NHR^(o) or —NH(C₁₋₄alkyl)NH₂; In someembodiments J^(R) is —NR(CH₂CH₂)N(R^(o))₂; In other embodiments J^(R) is—N(CH₃)CH₂CH₂N(R^(o))₂;

In other embodiments, each J^(R) is independently selected fromoptionally substituted —NH(5-6 membered heterocyclyl).

In certain embodiments, each J^(R) is 5-6 membered heterocyclyl contains1-2 nitrogen atoms. In some embodiments, the 5-6 membered heterocyclylis selected from pyrrolidine, piperidine, or piperazine.

In some embodiments J^(R) is optionally and independently substitutedwith R^(o).

In one embodiment of this invention, each X¹ and X² is independently—C(O)— or —NR— wherein one of X¹ or X² is —NR— and the other of X¹ or X²is —C(O)—.

In some embodiments X¹ is —C(O)— and X² is —NR—.

In other embodiments X¹ is —NR— and X² is —C(O)—.

In one embodiments of this invention, Q is a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-12 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In certain embodiments Q is C₆₋₁₀ aryl, C₃₋₁₀ cycloaliphatic, 5-14membered heteroaryl, or 5-14 membered heterocyclyl. In other embodimentsQ is C₆₋₁₀ aryl or 5-14 membered heteroaryl. In yet other embodiments Qis a 5-6 membered aryl or heteroaryl. In some embodiments, Q is 5-8membered heterocyclyl; in certain embodiments, 5-6 memberedheterocyclyl; In certain embodiments Q is phenyl.

In some embodiments of this invention, Q is substituted with up to 5J^(Q) groups wherein J^(Q) is CN, C₁₋₆alkyl, C₆₋₁₀aryl,—C₁₋₆alkyl-C₆₋₁₀aryl, C₁₋₄haloalkyl, —OR^(o), —N(R^(o))_(—SR) ^(o),—(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o),—C₁₋₆alkyl-(C₃₋₁₀heterocyclyl), —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o),—CON(R^(o))₂, —SO₂R^(o), —SO₂N(R^(o))₂, or C₁₋₆alkyl wherein up to threemethylene units are optionally and independently replaced by, —NR^(o)—,—O—, —S—, —SO—, SO₂—, or —CO— in a chemically stable arrangement.

In some embodiments, J^(Q) is selected from C₁₋₆alkyl, CN,C₁₋₄haloalkyl, —OR^(o), —N(R^(o))₂, —SR^(o), —(C₁₋₆alkyl)-OR^(o),—(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), C₆₋₁₀aryl,—C₁₋₆alkyl-C₆₋₁₀aryl, C₃₋₁₀cycloaliphatic,—C₁₋₆alkyl-(C₃₋₁₀cycloaliphatic), C₃₋₁₀heterocyclyl,—C₁₋₆alkyl-(C₃₋₁₀heterocyclyl), —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o),—CON(R^(o))₂, —SO₂R^(o), —SO₂N(R^(o))₂, or C₁₋₆alkyl wherein up to threemethylene units are optionally and independently replaced by, —NR^(o)—,—O—, —S—, —SO—, SO₂—, —CO—, cyclopropyl, C≡C, or C═C in a chemicallystable arrangement; each J^(Q) is optionally and independentlysubstituted with R^(o).

In some embodiments, J^(Q) is —SO₂N(R^(o))₂, —SO₂R^(o),—NR^(o)C(O)OR^(o), —C≡C—R^(o), —C═C—R^(o), phenyl, —O—Ph, —O—CH₂Ph,C₅₋₆heteroaryl, C₃₋₇heterocyclyl, or C₃₋₇cyclyoaliphatic.

In certain embodiments, J^(Q) is CN, C₁₋₆alkyl, —CF₃, —OCF₃, —OR^(o),—N(R^(o))₂, —SR^(o), —CH₂-halogen, —SCF₂, —(C₁₋₆alkyl)-N(R^(o))₂,C₆aryl, C₅₋₆heteroaryl, —C(O)OR^(o), —NR^(o) —COR^(o), or —CON(R^(o))₂.

In some embodiments R² is optionally substituted with up to 5 J^(Q)groups; in other embodiments, up to 3 J^(Q) groups; in yet otherembodiments, 0 or 1 J^(Q) groups.

In some embodiments R^(o) is selected from methyl, ethyl, n-propyl,isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, OH, halogen,—CH₂-pyrrolidine, COCH₃, —(C₁₋₄alkyl)₀₋₁-O(C₁₋₄alkyl),—(C₁₋₄alkyl)₀₋₁-O(C₁₋₄alkyl)OH, —(C₁₋₄alkyl)₀₋₁-O(C₁₋₄alkyl)OH,—(C₁₋₄alkyl)₀₋₁-NH(C₁₋₄alkyl), —(C₁₋₄alkyl)₀₋₁N(C₁₋₄alkyl)₂, or—(C₁₋₄alkyl)₀₋₁-NH

In some embodiments, the variables are as depicted in the Table Icompounds.

Accordingly, representative examples of compounds of formula I aredepicted in Table I. TABLE I

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

II-9

II-10

II-11

II-12

II-13

II-14

II-15

II-16

II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

II-25

II-26

II-27

II-28

II-29

II-30

II-31

II-32

II-33

II-34

II-35

II-36

II-37

II-38

II-39

II-40

II-41

II-42

II-43

II-44

II-45

II-46

II-47

II-48

II-49

II-50

II-51

II-52

II-53

II-54

II-55

II-56

II-57

II-58

II-59

II-60

II-61

II-62

II-63

II-64

II-65

II-66

II-67

II-68

II-69

II-70

II-71

II-72

II-73

II-74

II-75

II-76

II-77

II-78

II-79

II-80

II-81

II-82

II-83

II-84

II-85

II-86

II-87

II-88

II-89

II-90

II-91

II-92

II-93

II-94

II-95

II-96

II-97

II-98

II-99

II-100

II-101

II-102

II-103

II-104

II-105

II-106

II-107

II-108

II-109

II-110

II-111

II-112

II-113

II-114

II-115

II-116

II-117

II-118

II-119

II-120

II-121

II-122

II-123

II-124

II-125

II-126

II-127

II-128

II-129

II-130

II-131

II-132

II-133

II-134

II-135

II-136

II-137

II-138

II-139

II-140

II-141

II-142

II-143

II-144

II-145

II-146

II-147

II-148

II-149

II-150

II-151

II-152

II-153

II-154

II-155

II-156

II-157

II-158

II-159

II-160

II-161

II-162

II-163

II-164

II-165

II-166

II-167

II-168

II-169

II-170

II-171

II-172

II-173

II-174

II-175

II-176

II-177

II-178

II-179

II-180

II-181

II-182

III-1

III-2

III-3

III-4

III-5

III-6

III-7

III-8

III-9

III-10

III-11

III-12

III-13

III-14

III-15

III-16

III-17

III-18

III-19

III-20

III-21

III-22

III-23

III-24

III-25

III-26

III-27

III-28

III-29

III-30

III-31

III-32

III-33

III-34

III-35

III-36

III-37

III-38

III-39

III-40

III-41

III-42

III-43

III-44

III-45

III-46

III-47

III-48

III-49

III-50

III-51

III-52

III-53

III-54

IV-1

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds, asillustrated by the general scheme below, and the preparative examplesthat follow.

Reagents and conditions: (a) Pyridine, RT, 16 hours.

Scheme I above shows a general synthetic route that is used forpreparing the compounds 3a of this invention when R¹ is as describedherein. Compounds of formula 3a may be prepared by reaction of amrinone1 with an acid chloride in pyridine according to step (a) of Scheme I.The reaction is amenable to a variety of acid chlorides.

Compounds I-1 to I-67 and I-82 to I-85 were prepared according to thegeneral methods described in Scheme I.

Reagents and conditions: (a) NMP, xs (R⁰)₂NH, 160° C., 2 hours, μwawe.

Scheme II above shows a general synthetic route that is used forpreparing the compounds 3b of this invention when R⁰ is as describedherein. Compounds of formula 3b may be prepared by reaction of 1-20 withan excess of amine in NMP according to step (a) of Scheme II. Thereaction is amenable to a variety of amines.

Compounds I-68 to I-81 were prepared according to the general methodsdescribed in Scheme II.

Reagents and conditions: (a) MeI, Ag₂CO₃, CHCl₃, RT, 48 hours; (b)bis(pinacolato)diboron, Pd(Oac)₂, KOAc, DMF, 85° C., 3 hours; (c)R²-Hal, Pd(Pph₃)₄, aq. Na₂CO₃, toluene, EtOH, reflux, 4 hours.

Scheme III above shows a general synthetic route that is used forpreparing the compounds 7 of this invention when R² is as describedherein. Starting material 4, which may be prepared by methods describedby Warner, et al, J. Med. Chem. 1994, 37, 3090, is methylated accordingto step (a) of Scheme II. Compound of formula 6 is formed by reaction ofthe iodide 5 with bis(pinacolato)diboron in presence of palladium as acatalyst. The formation of derivatives 7 is achieved by treating theboronic ester derivatives 6 with a halide R²-Hal in the presence ofpalladium as a catalyst by using the Suzuki coupling methods that arewell known in the art. The reaction is amenable to a variety ofsubstituted halides R²-Hal.

Reagents and conditions: (a) aq. Hcl, 1,4-dioxane, reflux, 30 minutes;(b) H₂, 10% Pd/C, MeOH, EtOAc, 2 hours; (c) Pyridine, RT, 16 hours.

Scheme IV above shows a general synthetic route that has been used forpreparing compounds 10 of this invention when R¹ and R² are as describedherein. Demethylation of 7 in acidic conditions leads to the formationof 8, which is deprotected according to step (b). Finally, compounds offormula 10 may be prepared by reaction of derivatives 9 with an acidchloride 2 in pyridine. The reaction is amenable to a variety of acidchlorides 2.

Reagents and conditions: (a) H₂, 10% Pd/C, MeOH, EtOAc, 2 hours; (b)Pyridine, RT, 16 hours; (c) aq. Hcl, 1,4-dioxane, reflux, 30 minutes.

Scheme V above shows another general synthetic route that has been usedfor preparing compounds 10 of this invention when R¹ and R² are asdescribed herein. Intermediates 11, obtained by deprotection of amines7, react with an acid chloride 2 in pyridine. The reaction is amenableto a variety of acid chlorides 2. After demethylation of intermediates12 in acidic medium, pyridones 10 are obtained.

Reagents and conditions: (a) H₂, Pd(OH)₂/C, MeOH, RT, 5 hours; (b) Et₃N,DCM, RT, 10 minutes; (c) R²-Hal, Pd(Pph₃)₄, aq. Na₂CO₃, toluene, EtOH,reflux, 4 hours; (d) aq. Hcl, 1,4-dioxane, reflux, 30 minutes.

Scheme VI above shows another general synthetic route that has been usedfor preparing compounds 10 of this invention when R¹ and R² are asdescribed herein. Intermediate 13, obtained by deprotection of amine 6,reacts with an acid chloride 2 to form compounds of formula 14. Thereaction is amenable to a variety of acid chlorides 2. The formation ofderivatives 12 is achieved by treating the boronic ester derivatives 14with a halide R²-Hal in the presence of palladium as a catalyst by usingthe Suzuki coupling methods that are well known in the art. The reactionis amenable to a variety of substituted halides R²-Hal. Afterdemethylation of intermediates 12 in acidic medium, pyridones 10 areobtained.

Reagents and conditions: (a) (a) NMP, xs (R⁰)₂NH, 160° C., 2 hours,μwawe.

Scheme VII above shows a general synthetic route that is used forpreparing the compounds 16 of this invention when R² and R⁰ are asdescribed herein. Compounds of formula 16 may be prepared by reaction of15 with an excess of amine in NMP according to step (a) of Scheme VII.The reaction is amenable to a variety of amines.

Compounds II-1 to II-182 were prepared according to the general methodsdescribed in Schemes III, IV, V, VI and VII.

Reagents and conditions: (a) HOBt, DMAP, EDC, THF, RT, 16 hours.

Scheme VIII above shows a general synthetic route that has been used forpreparing compounds 19 of this invention when R, R¹ and R² are asdescribed herein. Starting material 17 may be prepared by methodssubstantially similar to those described in the literature by Church etal J. Org. Chem. 1995, 60, 3750. Compounds of formula 19 are preparedaccording to step (a) of scheme VIII.

Compounds III-1 to III-54 were prepared according to the general methoddescribed in Schemes VIII.

Reagents and conditions: (a) Pyridine, 0° C., 2 hours.

Scheme IX above shows a general synthetic route that is used forpreparing the compounds 21 of this invention when R¹ and R² are asdescribed herein. Compounds of formula 21 may be prepared by reaction ofderivatives 9 with a sulfonyl chloride 20 in pyridine. The reaction isamenable to a variety of sulfonyl chlorides 20.

Compound IV-1 was prepared according to the general method described inScheme IX.

This invention also provides compounds that can be used as intermediatesto synthesize compounds of this invention. Additionally, this inventionprovides processes for using these intermediate compounds to preparecompounds of this invention.

Specifically, a compound 22 can be used as an intermediate compound in aprocess for preparing a compound 23. Compound 23 can then be carried onto a compound of formula I.

wherein:R¹⁰ is an amino protective group;R¹¹ is H or C₁₋₆ alkyl or R¹⁰ and R¹¹ together with the nitrogen atom towhich they are bound form an amine protective group;R¹² is a hydroxyl protecting group; andR² is as defined herein.

In one embodiment, compound 22 is reacted with an appropriate compoundcomprising R² under appropriate reaction conditions to form compound 23.An example of an appropriate compound comprising R² is R²—X, wherein Xis an appropriate leaving group, such as a halo group. Appropriatereaction conditions are coupling conditions that allow bond formationbetween a boronic ester (or boronic acid) and R²—X. Appropriate leavinggroups and appropriate coupling conditions are known to skilledpractitioners (see, e.g., March, supra).

Compound 23 can be prepared by treating the boronic ester derivative 22with a halide R²-Hal in the presence of palladium as a catalyst by usingcoupling methods that are well known in the art, e.g., by using Suzukicoupling.

Scheme XI depicts an example of using Suzuki coupling conditions in amethod of this invention. In Scheme XI, R¹⁰ is a Cbz group, R¹¹ ishydrogen, and R¹² is a methyl group. Nevertheless, it should beunderstood that the reaction depicted in Scheme XI could be employedwith compound 22 in the place of compound 6 and compound 23 in the placeof 7.

(a) R²-Hal, Pd(Pph₃)₄, aq. Na₂CO₃, toluene, EtOH, reflux.

Compound 23 can be also prepared by treating the boronic esterderivative 22 with a nitrogen containing saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclcic ring (asdescribed in the R² definition) by reacting through a nitrogen atom inthe ring, in the presence of copper as a catalyst, e.g., by usingcoupling methods that are well known in the art (see, Chemick et al. J.Org. Chem. 2005, 1486) to provide 23 (wherein R² is a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving at least one nitrogen heteroatom; or an 8-12 membered saturated,partially unsaturated, or fully unsaturated bicyclic ring system havinghaving at least one nitrogen heteroatom and R² being optionallysubstituted with J^(R)). Scheme XII depicts an example of coopermediated coupling conditions in a method of this invention. In SchemeXII, R¹⁰ is a Cbz group, R¹¹ is hydrogen, and R¹² is a methyl group.Nevertheless, it should be understood that the reaction depicted inScheme XII could be employed with compound 22 in the place of compound 6and compound 23 in the place of 7.

(a) Cu (OAc)₂, Et₃N, O₂, CH₂Cl₂, r.t., 20 h.

In a process of this invention, compound 23 (and related compounds, suchas compound 7) is converted to a compound of formula I by methods knownto skilled practitioners including, but not limited to, those disclosedherein. In certain embodiments, the hydroxyl protective group incompound 23 is removed and then the amino protective group is removed.The resulting amine is reacted with an appropriate R¹ containingintermediate to provide the compound of formula I. For specific examplesof this embodiment, see Scheme IV and Scheme IX. In Scheme IV, R¹⁰ is aCbz group, R¹¹ is hydrogen, and R¹² is a methyl group. Nevertheless, itshould be understood that the reaction depicted in Scheme IV could beemployed with compound 23 in the place of compound 7.

In another embodiment, the amino protective group in compound 23 isremoved and then the resulting amine is reacted with an appropriate R¹containing intermediate to provide a compound X. A compound of formula Iis provided by removing the hydroxyl protective group from compound X.For a specific example of this embodiment, see Scheme V. In Scheme V,R¹⁰ is a Cbz group, R¹ is hydrogen, and R¹² is a methyl group.Nevertheless, it should be understood that the reaction depicted inScheme V could be employed with compound X in the place of compound 11and compound XX in the place of compound 12.

In embodiments wherein X¹ is —NR—, the amino protective group R¹¹ may bea group R¹—X²—. As would be recognized, in such embodiments, it wouldnot be necessary to remove the amino protective group and replace itwith an R¹ containing group. Accordingly, to obtain a compound offormula I, compound 23 would be reacted under conditions suitable toremove the hydroxyl protective group (thus providing the compound offormula I). In embodiments where the R^(o)C(═O)— group is incompatiblewith the boronic ester formation, the boronic ester could be formed withR¹⁰ being Cbz and then the Cbz group could be replaced with an R¹containing group after formation of the boronic ester. For a specificexample of this embodiment, see Scheme VI. In Scheme VI, R¹⁰ (incompound 14) is R^(o)C(═O)—, R¹¹ is hydrogen, and R¹² is a methyl group.Nevertheless, it should be understood that the reaction depicted inScheme VI could be employed with compound 22 in the place of compound 6.

Alternatively, R¹⁰ in 23 may be converted to R¹—X²—. That is, afunctional group in R¹⁰ could be converted to the desired R¹ containinggroup. Then, the hydroxyl protective group would be removed to providethe compound of formula I. For specific examples of this embodiment, seeScheme II and Scheme VII.

Compound 22 may be prepared by methods known to skilled practitionersincluding, but not limited to, methods disclosed herein. In oneembodiment, an iodo compound 24 is reacted under conditions to form theboronic ester 22 (Scheme XIII). For a specific example of suchconditions, see Scheme III. In Scheme III, R¹⁰ is a Cbz group, R¹¹ ishydrogen, and R¹² is a methyl group. Nevertheless, it should beunderstood that the reaction depicted in Scheme XII could be employedwith compound 22 in the place of compound 6 and compound 23 in the placeof 7.

It should be understood that instead of using a boronic ester 22 in aprocess of this invention, the corresponding boronic acid, could be used(Scheme XIV). The boronic acid could be used as a starting material orgenerated in situ. Compound 25 may be prepared by known methodsincluding, but not limited to, conversion of boronic ester 22 to boronicacid 25.

The protective groups protect the amino and hydroxyl functional groupsfrom reacting under conditions for converting the boronic ester or acidto the R² group. Many amino protective groups and hydroxyl protectivegroups are known to skilled practitioners. Examples of such protectivegroups may be found in T. W. Greene and P. G. M. Wutz, “ProtectiveGroups in Organic Synthesis”, 3^(rd) Edition, John Wiley & Sons, Inc.(1999) and earlier editions of this book and J. W. F. McOmie,“Protective Groups in Organic Synthesis”, Plenum Press (1973).

In certain embodiments, R¹⁰ is —C(O)R¹³ or —C(O)OR¹³, wherein:

R¹³ is:

unsubstituted C₁₋₆ alkyl,

C₁₋₆ alkyl substituted with C6-C10 aryl, or

C6-C10 aryl, wherein each C6-C10 aryl is optionally substituted withhalo, —CN, —NO₂, —N(R¹⁴)₂, unsubstituted C₁₋₆ alkyl, or —CF₃; and

R¹⁴ is H or unsubstituted C₁₋₆ alkyl.

Preferably, R¹⁰ is Cbz (carbobenzyloxy) or Boc (t-butoxycarbonyl).

In certain embodiments, R¹¹ is hydrogen.

In certain embodiments, R¹² is C₁₋₆ alkyl. Preferably, R¹² is methyl orethyl.

In a preferred embodiment, R¹⁰ is Cbz (carbobenzyloxy) or Boc(t-butoxycarbonyl); R¹¹ is hydrogen; and R¹² methyl.

Although certain exemplary embodiments are depicted and described aboveand herein, it will be appreciated that a compounds of the invention canbe prepared according to the methods described generally above usingappropriate starting materials by methods generally available to one ofordinary skill in the art.

As disclosed herein, the present invention provides compounds that areinhibitors of protein kinases, and thus the present compounds are usefulfor the treatment of diseases, disorders, and conditions including, butnot limited to an autoimmune, inflammatory, proliferative, orhyperproliferative disease or an immunologically-mediated disease.Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents. Such additionaltherapeutic agents include, but are not limited to an agent for thetreatment of an autoimmune, inflammatory, proliferative,hyperproliferative disease, or an immunologically-mediated diseaseincluding rejection of transplanted organs or tissues and AcquiredImmunodeficiency Syndrome (AIDS).

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a patient in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a Tec family (e.g., Tec, Btk,Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases kinase.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersible products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In certain embodiments, the composition comprises an effective amount ofthe compound of claim 1, and a pharmaceutically acceptable carrier,adjuvant, or vehicle. In a specific embodiment, the compound is presentin an amount to detectably inhibit a Tec family (e.g., Tec, Btk,Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase.

This invention also provides a pharmaceutical composition made bycombining a compound of this invention and a pharmaceutically acceptablecarrier, adjuvant, or vehicle and a process for making a pharmaceuticalcomposition comprising combining a compound of this invention and apharmaceutically acceptable carrier, adjuvant, or vehicle.

In yet another aspect, a method for the treatment or lessening theseverity of a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx,Txk/Rlk)-mediated diseases is provided comprising administering aneffective amount of a compound, or a pharmaceutically acceptablecomposition comprising a compound to a subject in need thereof. Themethods may employ a compound of Formula I or any of the other compoundsof this invention:

or a pharmaceutically accepted salt thereof, wherein

-   each R³ and R⁴ is independently H, halogen or C₁₋₄ aliphatic    optionally substituted with halogen, C₁₋₂aliphatic, OCH₃, NO₂, NH₂,    CN, NHCH₃, SCH₃, or N(CH)₂.-   R² is a 3-8-membered saturated, partially unsaturated, or fully    unsaturated monocyclic ring having 0-3 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or an 8-12 membered    saturated, partially unsaturated, or fully unsaturated bicyclic ring    system having 0-5 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; R² is optionally substituted with J^(R);    each X¹ and X² is independently —C(O)—, —NR—, or —SO₂— wherein one    of X¹ or X² is —NR— and the other of X¹ or X² is —C(O)— or —SO₂—;-   R is H, unsubstituted C₁₋₆ aliphatic;-   R¹ is -T-Q;-   T is a bond or C₁₋₆ aliphatic, wherein up to three methylene units    of the chain are optionally and independently replaced by G or G′    wherein G is —NR⁵—, —O—, —S—, —SO—, SO₂—, —CS—, or —CO—; G′ is    cyclopropyl, C≡C, or C═C; T is optionally substituted with-   Q is independently hydrogen, a C₁₋₆ aliphatic group, a 3-8-membered    saturated, partially unsaturated, or fully unsaturated monocyclic    ring having 0-3 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or an 8-12 membered saturated, partially    unsaturated, or fully unsaturated bicyclic ring system having 0-5    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    Q is optionally substituted with J^(Q); and-   R⁵ is optionally substituted R, C₆₋₁₀ aryl, C₃₋₁₀ cycloaliphatic,    5-14 membered heteroaryl, or 5-14 membered heterocyclyl; or two R⁵    groups, together with the atom(s) to which they are attached, form    an optionally substituted 3-7 membered monocyclic or 8-14 membered    bicyclic ring;    wherein the optional substituents J^(R), J^(T), and J^(Q) are    defined herein.

In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutically acceptable composition is that amounteffective for a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx,Txk/Rlk)-mediated disease. The compounds and compositions, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk,Bmx, Txk/Rlk)-mediated disease. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. The compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and I) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of protein kinases. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of Tecfamily (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase, and thus,without wishing to be bound by any particular theory, the compounds andcompositions are particularly useful for treating or lessening theseverity of a disease, condition, or disorder where activation of one ormore of a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinaseis implicated in the disease, condition, or disorder. When activation ofTec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) is implicated ina particular disease, condition, or disorder, the disease, condition, ordisorder may also be referred to as a “Tec family (e.g., Tec, Btk,Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediated disease” or disease symptom.Accordingly, in another aspect, the present invention provides a methodfor treating or lessening the severity of a disease, condition, ordisorder where activation or one or more of Tec family (e.g., Tec, Btk,Itk/Emt/Tsk, Bmx, Txk/Rlk) is implicated in the disease state.

Also without wishing to be bound by any particular theory, the compoundsand compositions of this invention are particularly useful for treatingor lessening the severity of a disease, condition, or disorder whereactivation of Itk kinase is implicated in the disease, condition, ordisorder and are particularly useful for inhibiting Itk selectively overBtk and Rlk (see, Examples 14-16 and 18).

The activity of a compound utilized in this invention as an inhibitor ofa Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of activated Tec family (e.g., Tec, Btk, Itk/Emt/Tsk,Bmx, Txk/Rlk) kinase. Alternate in vitro assays quantitate the abilityof the inhibitor to bind to a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk,Bmx, Txk/Rlk) kinase. Inhibitor binding may be measured byradiolabelling the inhibitor prior to binding, isolating theinhibitor/Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk),complex and determining the amount of radiolabel bound. Alternatively,inhibitor binding may be determined by running a competition experimentwhere new inhibitors are incubated with a Tec family (e.g., Tec, Btk,Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase bound to known radioligands.

The term “measurably inhibit”, as used herein means a measurable changein a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinaseactivity between a sample comprising said composition and a Tec family(e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase and an equivalentsample comprising a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx,Txk/Rlk) kinase in the absence of said composition.

The term “Tec family tyrosine kinases-mediated condition”, as usedherein means any disease or other deleterious condition in which Tecfamily kinases are known to play a role. Such conditions include,without limitation, autoimmune, inflammatory, proliferative, andhyperproliferative diseases and immunologically mediated diseasesincluding rejection of transplanted organs or tissues and AcquiredImmunodeficiency Syndrome (AIDS).

For example, Tec family tyrosine kinases-mediated conditions includediseases of the respiratory tract including, without limitation,reversible obstructive airways diseases including asthma, such asbronchial, allergic, intrinsic, extrinsic and dust asthma, particularlychronic or inveterate asthma (e.g., late asthma airwayshyper-responsiveness) and bronchitis. Additionally, Tec family tyrosinekinases diseases include, without limitation, those conditions byinflammation of the nasal mucus membrane, including acute rhinitis,allergic, atrophic thinitis and chronic rhinitis including rhinitiscaseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca andrhinitis medicamentosa; membranous rhinitis including croupous,fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis,seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotorrhinitis, sarcoidosis, farmer's lung and related diseases, fibroid lungand idiopathic interstitial pneumonia.

Tec family tyrosine kinases-mediated conditions also include diseases ofthe bone and joints including, without limitation, (pannus formation in)rheumatoid arthritis, seronegative spondyloarthropathis (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, and systemic sclerosis.

Tec family kinases-mediated conditions also include diseases anddisorders of the skin, including, without limitation, psoriasis,systemic sclerosis, atopical dermatitis, contact dermatitis and othereczematous dermatitis, seborrhoetic dermatitis, Lichen planus,Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria,angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis,Alopecia, greata and vernal conjunctivitis.

Tec family tyrosine kinases-mediated conditions also include diseasesand disorders of the gastrointestinal tract, including, withoutlimitation, Coeliac disease, proctitis, eosinophilic gastro-enteritis,mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis,food-related allergies which have effects remote from the gut, e.g.,migraine, rhinitis and eczema.

Tec family tyrosine kinases-mediated conditions also include thosediseases and disorders of other tissues and systemic disease, including,without limitation, multiple sclerosis, atherosclerosis, acquiredimmunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus,erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type Idiabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,lepromatous leprosy, sezary syndrome and idiopathic thrombocytopeniapurpura, restenosis following angioplasty, tumours (for exampleleukemia, lymphomas), artherosclerosis, and systemic lupuserythematosus.

Tec family tyrosine kinases-mediated conditions also include allograftrejection including, without limitation, acute and chronic allograftrejection following for example transplantation of kidney, heart, liver,lung, bone marrow, skin and cornea; and chronic graft versus hostdisease.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

Additional therapeutic agents that may be used in the methods of thisinvention include, but are not limited to, agents for the treatment ofan autoimmune, inflammatory, proliferative, hyperproliferative disease,or an immunologically-mediated disease including rejection oftransplanted organs or tissues and Acquired Immunodeficiency Syndrome(AIDS), wherein the additional therapeutic agent is appropriate for thedisease being treated; and the additional therapeutic agent isadministered together with said composition as a single dosage form orseparately from said composition as part of a multiple dosage form.

For example, chemotherapeutic agents or other anti-proliferative agentsmay be combined with the compounds of this invention to treatproliferative diseases and cancer. Examples of known chemotherapeuticagents include, but are not limited to, For example, other therapies oranticancer agents that may be used in combination with the inventiveanticancer agents of the present invention include surgery, radiotherapy(in but a few examples, gamma.-radiation, neutron beam radiotherapy,electron beam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes, to name a few), endocrine therapy, biologicresponse modifiers (interferons, interleukins, and tumor necrosis factor(TNF) to name a few), hyperthermia and cryotherapy, agents to attenuateany adverse effects (e.g., antiemetics), and other approvedchemotherapeutic drugs, including, but not limited to, alkylating drugs(mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan,Ifosfamide), antimetabolites (Methotrexate), purine antagonists andpyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile,Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine,Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan),antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas(Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin),enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide,and Megestrol), Gleevec™, adriamycin, dexamethasone, andcyclophosphamide. For a more comprehensive discussion of updated cancertherapies see, http://www.nci.nih.gov/, a list of the FDA approvedoncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, andThe Merck Manual, Seventeenth Ed. 1999, the entire contents of which arehereby incorporated by reference.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole,bromocriptine, pergolide, trihexephendyl, and amantadine; agents fortreating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such asalbuterol and Singulair®; agents for treating schizophrenia such aszyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agentssuch as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporine, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating implantable medical devices, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device.

Vascular stents, for example, have been used to overcome restenosis(re-narrowing of the vessel wall after injury). However, patients usingstents or other implantable devices risk clot formation or plateletactivation. These unwanted effects may be prevented or mitigated bypre-coating the device with a pharmaceutically acceptable compositioncomprising a kinase inhibitor. Suitable coatings and the generalpreparation of coated implantable devices are described in U.S. Pat.Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Tec family (e.g.,Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) activity in a biological sample ora patient, which method comprises administering to the patient, orcontacting said biological sample with a compound of formula I or acomposition comprising said compound. The term “biological sample”, asused herein, includes, without limitation, cell cultures or extractsthereof; biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof.

Inhibition of Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)kinase activity in a biological sample is useful for a variety ofpurposes that are known to one of skill in the art. Examples of suchpurposes include, but are not limited to, blood transfusion,organ-transplantation, biological specimen storage, and biologicalassays.

EXAMPLES

As used herein, the term “Rt(min)” refers to the HPLC retention time, inminutes, associated with the compound. Unless otherwise indicated, theHPLC method utilized to obtain the reported retention time is asfollows:

Column: Ace 5 C8, 15 cm×4.6 mm id

Gradient: 0-100% acetonitrile+methanol (50:50) (20 mM Tris phosphate atpH 7.0)

Flow rate: 1.5 ml/min

Detection: 225 nm

Example 1

4-tert-Butyl-N-(6-oxo-1,6-dihydro-[3,4′]bipyridinyl-5-yl)-benzamide I-11

Amrinone (200 mg, 1.07 mmol) was suspended in pyridine (5 mL) and4-tert-butylbenzoyl chloride (209 μL, 1.07 mmol) was added. The reactionmixture was stirred overnight at room temperature. The solid wasfiltered and rinsed with MeOH to give the title compound as a pink solid(33 mg, 9% yield). MS (ES⁺) m/e=348. ¹H NMR (DMSO-d₆) δH 1.43 (9H, s),7.57-7.62 (4H, m), 7.81 (1H, s), 7.88 (2H, d), 8.59 (2H, d), 8.78 (1H,d), 9.32 (1H, s), 12.61 (1H, s).

Example 2

N-(1,2-dihydro-2-oxo-5-(pyridin-4-yl)pyridin-3-yl)-4-(piperidin-1-yl)benzamideI-68

4-Bromo-N-(1,2-dihydro-2-oxo-5-(pyridin-4-yl)pyridin-3-yl)benzamide (30mg, 0.081 mmol) I-20 was placed in a microwave tube equipped with astirrer bar. NMP (0.75 mL) was added, followed by piperidine (1.5 mL).The reaction vessel was heated at 160° C. for 2 hours in a microwave.After cooling, the solvent and excess piperidine were removed in vacuo.The crude compound was recrystallized from methanol to give the titlecompound as a white solid (13 mg, 43% yield).). MS (ES⁺) m/e=375. ¹H NMR(DMSO-d₆) δH 1.54-1.65 (6H, m), 3.30-3.38 (4H, m), 7.02 (2H, d), 7.61(2H, d) 7.72-7.80 (1H, m), 7.78 (2H, d), 8.59 (2H, d), 8.77 (1H, d),9.13 (1H, s), 12.58 (1H, bs).

A variety of other compounds of Formula I have been prepared by methodssubstantially similar to those described herein. The characterizationdata for these compounds is summarized in Table I-A below and includesHPLC, LC/MS (observed) and ¹H NMR data.

¹H NMR data is summarized in Table I-A below wherein ¹H NMR data wasobtained at 400 Mhz in deuterated DMSO, unless otherwise indicated, andwas found to be consistent with structure. Compound numbers correspondto the compound numbers listed in Table 1. TABLE I-A CharacterizationData for Selected Compounds of Formula I Compound No I- M+1(obs) Rt(min)¹H-NMR 1 292 7.5 (CDCl₃) 7.02-7.65(6H, m), 7.95-7.99(2H, m),8.69-8.70(2H, m), 9.11(1H, br s), 9.16(1H, br s), 11.43(1H, br s) 2 3227.7 3.85(3H, s), 7.10(2H, d), 7.61(2H, d), 7.80(1H, s), 7.93(2H, d),8.58(2H, d), 8.75(1H, m), 9.28(1H, s), 12.60(1H, s) 3 306 7.5 3.85(2H,s), 7.19-7.34(5H, m), 7.52(2H, d), 7.70(1H, s), 8.54(1H, d), 8.72(1H,s), 9.58(1H, s), 12.45(1H, s) 4 298 8.1 1.25-1.40(5H, m), 1.64(1H, brd), 1.72(2H, br d), 1.80(2H, br d), 2.60-2.67(1H, m), 7.55(2H, d),7.71(1H, s), 8.55(2H, d), 8.72(1H, s), 9.18(1H, s), 12.40(1H, br s) 5340 8.2 4.86(2H, s), 7.58-7.65(4H, m), 7.83(1H, s), 7.97(2H, m),8.59(2H, m), 8.76(1H, s), 9.44(1H, s), 12.63(1H, br s) 6 320 8.71.22(3H, t), 2.70(2H, q), 7.41(2H, d), 7.61(2H, d), 7.81(1H, d),7.87(2H, d), 8.58(2H, d), 8.77(1H, d), 9.33(1H, s), 12.62(1H, br s) 7342 8.7 7.62-7.69(4H, m), 7.84(1H, s), 8.02(2H, t), 8.10(1H, d),8.16(1H, d), 8.59-8.62(3H, m), 8.82(1H, s), 9.59(1H, s), 12.65(1H, s) 8306 8.0 2.40(3H, s), 7.37(2H, d), 7.86(2H, d), 8.01(2H, d), 8.09(1H, s),8.75(2H, d), 8.83(1H, d), 9.39(1H, s), 12.88(1H, s) 9 317 7.4 7.62(2H,d), 7.87(1H, s), 8.04(2H, d), 8.11(2H, d), 8.59(2H, d), 8.72(1H, s),9.72(1H, s), 12.63(1H, s) 10 334 9.2 0.91(3H, t), 1.62(2H, m), 2.64(2H,t), 7.38(2H, d), 7.61(2H, d), 7.81(1H, s), 7.87(2H, d), 8.59(2H, d),8.77(1H, d), 9.33(1H, s), 12.61(1H, s) 12 368 9.3 7.44(1H, t), 7.53(2H,t), 7.63(2H, d), 7.77(2H, d), 7.84(1H, d), 7.88(2H, d), 8.05(2H, d),8.60(2H, d), 8.79(1H, d), 9.47(1H, d), 12.64(1H, br s) 13 306 8.22.41(3H, s), 7.44-7.48(2H, m), 7.74-7.78(2H, m), 8.21-8.25(3H, m),8.82-8.86(3H, m), 9.41(1H, s), 13.02(1H, s) 14 336 8.3 1.37(3H, t),4.12(2H, q), 7.19(1H, d), 7.44-7.51(3H, m), 7.61(2H, d), 7.83(1H, d),8.59(2H, d), 8.74(1H, d), 9.37(1H, s), 12.61(1H, s) 15 374 8.67.60-7.84(3H, m), 8.05-8.26(5H, m), 8.76-8.84(3H, m), 9.73(1H, s),13.00(1H, s) 16 376 9.0 7.66(1H, d), 7.72(1H, t), 7.93(1H, s), 8.02(1H,d), 8.20(2H, d), 8.26(1H, s), 8.81-8.83(3H, m), 9.78(1H, s), 12.99(1H,s) 17 390 8.8 4.00(3H, s), 7.43(1H, d), 8.14-8.28(5H, m), 8.74-8.82(3H,m), 9.75(1H, s), 12.93(1H, br s) 18 376 9.0 7.55-7.57(2H, m),8.09-8.11(2H, m), 8.18-8.19(2H, m), 8.23(1H, m), 8.81-8.83(3H, m),9.66(1H, s), 12.97(1H, s) 19 320 8.0 2.79-2.92(4H, m), 7.18(1H, m),7.28-7.30(4H, m), 8.13-8.14(3H, m), 8.75-8.79(2H, m), 8.87(1H, s),9.64(1H, s), 12.82(1H, s) 20 372 8.6 7.61(2H, dd), 7.77(2H, d), 7.84(1H,d), 7.90(2H, d), 8.58(2H, dd), 8.73(1H, d), 9.52(1H, s), 12.61(1H, br s)21 350 8.7 1.30(6H, s), 4.75(1H, m), 7.07(2H, d), 7.91(2H, d),8.20-8.21(3H, m), 8.82-8.86(3H, m), 9.32(1H, s), 12.98(1H, s) 22 384 9.37.11-7.15(4H, m), 7.25(1H, m), 7.45-7.49(2H, m), 7.94-8.02(4H, m),8.09(1H, s), 8.70-8.82(2H, m), 8.82(1H, m), 9.40(1H, s), 12.86(1H, s) 23332 8.5 1.31(1H, m), 1.48(1H, m), 2.37(1H, m), 2.79(1H, m),7.16-7.22(3H, m), 7.28-7.32(2H, m), 8.12-8.14(3H, m), 8.80(2H, d),8.87(1H, m), 9.99(1H, s), 12.81(1H, s) 24 374 10.3 1.27(1H, m),1.40-1.49(4H, m), 1.72(1H, m), 1.80-1.82(4H, m), 2.60(1H, m),7.41-7.44(3H, m), 7.86-7.92(6H, m), 8.79(1H, s), 9.33(1H, s), 12.70(1H,s) 25 326 7.7 7.40-7.67(6H, m), 7.83(1H, s), 8.59(2H, d), 8.80(1H, d),9.67(1H, s), 12.6(1H, s) 26 293 6.1 7.58-7.63(3H, m), 7.86(1H, s),8.31(1H, d), 8.59(2H, d), 8.74(1H, d), 8.78(1H, d), 9.10(1H, s),9.74(1H, s), 12.6(1H, s) 27 326 8.4 7.61-7.65(4H, m), 7.84(1H, d),7.98(2H, d), 8.58(2H, d), 8.73(1H, d), 9.52(1H, s), 12.62(1H, bs) 28 4266.7 2.93(3H, s), 3.17(3H, s), 7.62(2H, d), 7.77(1H, d), 7.85(2H, d),7.93(2H, d), 8.27(1H, s), 8.59(2H, d), 8.75(1H, d), 9.60(1H, s),12.61(1H, bs) 29 293 7.4 7.62(2H, d), 7.74(1H, m), 7.83(1H, m), 8.13(1H,m), 8.20(1H, m), 8.60(2H, d), 8.78(1H, d), 8.92(1H, d), 10.76(1H, s),12.68(1H, s) 30 327 7.1 7.61(2H, dd), 7.70(1H, d), 7.86(1H, d), 8.34(1H,dd), 8.58(2H, d), 8.71(1H, d), 8.93(1H, d), 9.87(1H, s), 12.60(1H, br s)31 327 — 7.35(1H, m), 7.70(2H, m), 7.80(2H, m), 8.00(1H, s), 8.68(2H,m), 8.90(1H, s), 9.80(1H, m) 32 327 — 7.55(2H, m), 7.70(1H, m), 7.90(2H,br s), 8.05(1H, br s), 8.70(2H, m), 8.90(1H, s), 9.80(1H, m) 33 327 —7.55(1H, m), 7.65(2H, m), 7.90(2H, m), 8.09(1H, s), 8.74(3H, m), 9.7(1H,s) 34 297 — 7.23(1H, m), 7.90(1H, s), 8.05(1H, s), 8.20(3H, m), 8.75(1H,s), 8.80(2H, m), 9.57(1H, s) 35 281 — 6.75(1H, m), 7.35(1H, m), 7.90(2H,m), 8.05(2H, m), 8.70(2H, m), 8.75(1H, s), 9.23(1H, s) 36 377 — 7.65(1H,m), 8.15(2H, m), 8.20(1H, m), 8.80(2H, m), 8.85(1H, s), 10.00(1H, s)7.75(2H, m), 37 316 — 7.60(2H, s), 7.76(1H, m), 7.85(1H, s), 8.10(1H,m), 8.25(1H, m), 8.41(1H, s), 8.58(2H, m), 8.75(1H, s), 9.85(1H, s) 38369 — (CD₃OD) 3.20(3H, s), 7.20(1H, s), 7.70(1H, s), 8.20-8.40(6H, m),8.70(2H, d), 8.80(1H, d) 39 310 — 7.40(2H, m), 8.10(2H, m), 8.20(3H, m),8.80(3H, m), 9.60(1H, s) 40 372 8.6 7.54(1H, t), 7.58-7.65(2H, m),7.80-7.88(2H, m), 794(1H, d), 8.13(1H, s), 8.57-8.63(2H, m), 8.73(1H,s), 9.62(1H, s) 41 335 — — 42 359 — — 43 360 — 7.80(1H, m), 8.00(1H, m),3.18(2H, m), 8.25(3H, m), 8.80(3H, m), 9.85(1H, s) 44 309 — 7.42(2H, m),7.55(2H, m), 7.65(1H, m), 7.80(1H, s), 8.00(1H, m), 8.60(2H, m),8.90(1H, s), 9.70(1H, m) 45 335 8.0 3.02(6H, s), 6.80(2H, d), 7.60(2H,dd), 7.75-7.80(3H, m), 8.58(2H, d), 8.77(1H, d), 9.11(1H, s), 12.57(1H,br s) 46 398 — (CDCl₃) 5.20(2H, s), 7.10(3H, d), 7.50(5H, m), 8.00(3H,m), 8.70(2H, d), 9.10(2H, d) 47 307 — 6.70(2H, d), 7.40(2H, d), 7.60(2H,m), 8.00(1H, s), 8.40(2H, d), 8.50(1H, s), 9.50(1H, s), 48 348 —2.10(3H, s), 7.60(2H, d), 7.70(3H, m), 7.90(2H, d), 8.60(2H, d),8.80(1H, s), 9.30(1H, s), 10.30(1H, s) 49 348 — 2.10(3H, s), 7.50(1H,m), 7.60(3H, s), 7.80(1H, s), 7.90(2H, d), 8.20(1H, s), 8.60(2H, d),8.80(1H, s), 9.30(1H, s), 10.20(1H, s) 50 372 — 9.00(1H, s), 8.70(1H,s), 8.60(2H, d), 7.80(2H, d), 7.75(2H, d), 7.60(2H, d), 7.40-7.50(3H,m), 7.30(1H, t), 2.70(3H, s) 51 382 — 7.10(1H, d), 7.45(2H, d), 7.50(3H,m), 7.60(2H, m), 7.70(2H, d), 7.80(1H, d), 8.60(2H, d), 8.70(1H, d),9.30(1H, s) 52 376 — — 53 358 — — 54 373 — — 55 — — — 56 256 — 0.80(4H,m), 2.20(1H, m), 7.90(2H, m), 7.95(1H, s), 8.70(2H, m), 8.78(1H, s),9.75(1H, s) 57 311 — 7.55(1H, m), 7.90(2H, m), 8.10(1H, m), 8.40(2H, m),8.70(2H, m), 9.90(1H, s), 10.0(1H, s) 58 359 — 7.43(1H, m), 7.65(1H, m),7.85(3H, m), 8.05(1H, m), 8.25(1H, m), 8.70(4H, m), 8.95(1H, br s),10.20(1H, s) 59 311 — 7.65(1H, s), 7.80(1H, m), 7.92(2H, m), 8.10(1H, brs), 8.45(1H, m), 8.75(3H, m), 9.90(1H, s) 60 324 — 1.35(3H, t), 2.20(3H,s), 4.45(2H, q), 6.80(1H, s), 7.95(2H, m), 8.05(1H, br s), 8.70(3H, m),9.20(1H, s) 61 409 — — 62 — — 3.90(3H, s), 6.90(1H, d), 7.40(2H, d),7.50(1H, s), 7.90(2H, d), 8.00(1H, s), 8.70(2H, d), 8.80(1H, s),9.20(1H, s), 9.80(1H, s) 63 327 — 2.60(2H, s), 6.70(1H, s), 8.00(1H, s),8.10(2H, d), 8.60(1H, s), 8.80(2H, d) 64 254 — 3.00(3H, s), 7.80(1H, s),7.95(1H, s), 8.00(2H, d), 8.50(1H, s), 8.70(2H, d) 65 359 — 1.30(3H, t),2.80(2H, q), 6.80(1H, s), 7.10(1H, m), 7.40(2H, d), 7.50(1H, s),7.60(2H, d), 7.80(1H, m), 8.60(2H, d), 11.40(1H, s) 66 407 — 1.50(9H,s), 7.40(1H, m), 7.50(1H, d), 7.60(2H, d), 7.70(1H, m), 7.80(1H, s),8.10(1H, s), 8.60(2H, d), 8.80(1H, s), 9.30(1H, s), 9.60(1H, s) 67 412 —3.80(2H, s), 5.20(2H, s), 6.90(1H, m), 7.10(1H, d), 7.20-7.30(5H, m),7.40(2H, d), 7.50(2H, d), 7.70(1H, s), 8.60(2H, d), 8.70(1H, s),9.25(1H, s) 69 361 8.8 1.96-2.00(4H, m), 3.29-3.35(4H, m), 6.63(2H, d),7.60(2H, d), 7.75-7.79(3H, m), 8.58(2H, d), 8.77(1H, d), 9.08(1H, s),12.45(1H, br s) 70 390 7.4 2.23(3H, s), 2.43-2.48(4H, m), 3.28-3.34(4H,m), 7.05(2H, d), 7.60(2H, d), 7.76-7.84(3H, m), 8.58(2H, d), 8.77(1H,d), 9.16(1H, s), 12.58(1H, br s) 71 376 6.3 2.81-2.86(4H, m),3.20-3.26(4H, m), 7.02(2H, d), 7.60(2H, d), 7.75-7.82(3H, m), 8.58(2H,d), 8.77(1H, d), 9.14(1H, s) 72 391 7.1 1.38-1.48(2H, m), 1.76-1.84(2H,m), 3.00-3.07(2H, m), 3.66-3.76(3H, m), 4.73(1H, bs), 7.03(2H, d),7.54(2H, d), 7.75(2H, d), 7.85(1H, d), 8.52(2H, d), 8.68(1H, d),9.28(1H, br s) 73 377 7.5 3.25-3.29(4H, m), 3.72-3.77(4H, m), 7.06(2H,d), 7.60(2H, dd), 7.78(1H, d), 7.82(2H, d), 8.58(2H, dd), 8.76(1H, d),9.18(1H, s), 12.56(1H, br s) 74 476 7.0 0.95(6H, t), 2.39-2.56(12H, m),3.26-3.39(4H, m), 7.03(2H, d), 7.60(2H, d), 7.75-7.82(3H, m), 8.58(2H,d), 8.77(1H, d), 9.15(1H, s) 75 444 6.8 1.47-1.59(2H, m), 1.63-1.86(4H,m), 1.92-2.06(2H, m), 2.89(2H, t), 3.26-3.39(5H, m), 3.82-3.98(2H, m),7.06(2H, d), 7.60(2H, d), 7.76-7.82(3H, m), 8.59(2H, d), 8.77(1H, d),9.15(1H, s), 12.58(1H, br s) 76 389 9.5 1.44-1.49(4H, m), 1.70-1.77(4H,m), 3.50-3.56(4H, m), 6.79(2H, d), 7.59(2H, d), 7.73-7.77(3H, m),8.57(2H, d), 8.76(1H, d), 9.08(1H, s) 77 449 7.8 1.69(2H, quintet),2.36(2H, t), 3.22(3H, s), 3.27-3.38(10H, m), 7.04(2H, d), 7.60(2H, d),7.76-7.82(3H, m), 8.58(2H, d), 8.76(1H, d), 9.16(1H, s), 12.42(1H, v brs) 78 390 6.4 1.74-1.81(2H, m), 2.62(2H, t), 2.85(2H, t), 3.29-3.37(2H,m), 3.53(2H, t), 3.61(2H, t), 6.81(2H, d), 7.59(2H, d), 7.72-7.76(3H,m), 8.58(2H, d), 8.77(1H, d), 9.07(1H, s) 79 392 6.5 1.68(2H, m),2.14(6H, s), 2.29(2H, t), 3.09(2H, dt), 6.41-6.48(1H, m), 6.63(2H, d),7.50-7.54(2H, m), 7.66(2H, d), 7.82-7.86(1H, m), 8.46-8.51(2H, m),8.63-8.68(1H, m), 9.21(1H, br s) 80 364 6.0 1.63(2H, m), 2.65(2H, t),3.13(2H, dt), 6.50(1H, t), 6.65(2H, d), 7.58(2H, d), 7.68(2H, d),7.76(1H, d), 8.57(2H, d), 8.75(1H, d), 9.05(1H, s) 81 464 7.02.50-2.58(6H, m), 3.25-3.29(4H, m), 3.42(2H, t), 3.46-3.52(2H, m),3.56(2H, t), 4.62(1H, br s), 7.04(2H, d), 7.60(2H, d), 7.77-7.82(3H, m),8.58(2H, d), 8.76(1H, d), 9.17(1H, s) 82 391 7.4 3.19(4H, m),3.5-4.0(masked protons), 4.43(2H, s), 7.67-7.71(2H, m), 7.97(2H, m),8.04-8.10(3H, m), 8.74-8.82(3H, m), 9.51(1H, s), 12.87(1H, br s) 83 3906.4 (DMSO+D₂O) 3.00(4H, m), 3.22(4H, m), 4.03(2H, s), 7.58(2H, d),7.96(2H, d), 8.09-8.12(3H, m), 8.69(2H, d), 8.79(1H, s) 84 392 6.7 (D₂O)2.68(3H, s), 2.77(3H, s), 3.43-3.51(4H, m), 4.41(2H, s), 7.58(2H, d),7.90(2H, d), 8.04(1H, m), 8.09(2H, m), 8.60(2H, m), 8.70(1H, m) 85 4066.7 (D₂O) 2.08(2H, m), 2.60(3H, s), 2.73(3H, s), 2.98(2H, m), 3.19(2H,m), 4.35(2H, m), 7.55(2H, m), 7.88(2H, m), 8.01-8.10(3H, m),8.59-8.69(3H, m)

Example 3

(5-Iodo-2-methoxy-pyridin-3-yl)-carbamic acid benzyl ester

(5-Iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester (3.68g, 9.94 mmol) was dissolved in chloroform (50 mL) at room temperatureunder nitrogen in the dark (foil wrapped). Silver carbonate (3.70 g,13.2 mmol) was added followed by iodomethane (6.2 mL, 99.4 mmol). Thereaction mixture was allowed to stir at room temperature for 48 hours.The silver salts were removed by filtration through a pad of celite,washing with more chloroform and the filtrate concentrated in vacuo. Theresidue was purified by column chromatography to give the title compoundas a white solid (3.14 g, 82% yield). MS (ES⁺) m/e=385. ¹H NMR (CDCl₃)δH 3.97 (3H, s), 5.23 (2H, s), (1H, br s), 7.35-7.47 (5H, m), 8.00 (1H,s), 8.64 (1H, br s).

Example 4

[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-carbamicacid benzyl ester

(5-Iodo-2-methoxy-pyridin-3-yl)-carbamic acid benzyl ester (1 g, 2.6mmol), bis(pinacolato)diboron (727 mg, 2.86 mmol), KOAc (766 mg, 7.81mmol) and Pd(Oac)₂ (18 mg, 3 mol %) were suspended in anhydrous DMF (20mL). This was degassed by slowly bubbling nitrogen through the systemfor 30 minutes and then heated to 85° C. for 3 hours. The reaction wascooled to room temperature and diluted with water. The reaction mixturewas extracted with EtOAc (×3), dried over MgSO₄, filtered andconcentrated in vacuo. Purification by column chromatography gave thetitle compound as a white solid (501 mg, 50% yield). MS (ES⁺) m/e=385.¹H NMR (DMSO-d₆) δH 1.34 (12H, s), 4.03 (3H, s), 5.24 (2H, s), 7.15 (1H,br s), 7.34-7.46 (5H, m), 8.21 (1H, s), 8.63 (1H

Example 5

[2-Methoxy-5-(2-methylsulfanyl-pyrimidin-4-yl)-pyridin-3-yl]-carbamicacid benzyl ester

[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-carbamicacid benzyl ester (377 mg, 0.98 mmol), 4-chloro-2-thiomethylpyrimidine(171 μL, 1.47 mmol) and Pd(Pph₃)₄ (113 mg, 10 mol %) were dissolved intoluene (15 mL) and EtOH (3 mL). Na₂CO₃ (717 mg, 6.77 mmol) in water (6mL) was added and the reaction mixture was heated to reflux for 4 hours.After cooling down to room temperature, the reaction mixture was dilutedwith water and extracted with EtOAc (×3). The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo. The residuewas absorbed onto silica and purified by column chromatography to givethe title compound as an off-white solid (261 mg, 70% yield). MS (ES⁺)m/e=383. ¹H NMR (DMSO-d₆) δH 2.67 (3H, s), 4.09 (3H, s), 5.27 (2H, s),7.30-7.47 (7H, m), 8.54 (1H, d), 8.67 (1H, s), 9.01 (1H, br s).

Example 6

[5-(2-Methylsulfanyl-pyrimidin-4-yl)-2-oxo-1,2-dihydro-pyridin-3-yl]-carbamicacid benzyl ester II-3

[2-Methoxy-5-(2-methylsulfanyl-pyrimidin-4-yl)-pyridin-3-yl]-acid benzylester (20 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL) and water(300 μL). Concentrated HCl (100 μL) was added and the reaction mixturewas heated to reflux for 30 minutes. The reaction mixture was cooleddown to room temperature and water was added. The obtained precipitatewas isolated by filtration and dried under vacuum to give the titlecompound as a yellow solid (12.9 mg, 67% yield). MS (ES⁺) m/e=369. ¹HNMR (DMSO-d₆) δH 2.56 (3H, s), 5.20 (2H, s), 7.38-7.46 (5H, m), 7.60(1H, d), 8.10 (1H, br d), 8.56 (1H, d), 8.61 (1H, s), 8.69 (1H, s),12.52 (1H, br d).

Example 7

2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine

[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-carbamicacid benzyl ester (506 mg, 1.32 mmol) was dissolved in methanol (10 mL).Pd(OH)₂ on carbon (51 mg, 10 mol %) was added and the reaction wasdegassed with nitrogen. The nitrogen atmosphere was replaced by hydrogenand the reaction mixture was stirred at room temperature for 5 hours.The palladium residue was removed by filtration through a path ofCelite, rinsing with more methanol. The filtrate was concentrated invacuo to give the title compound as an off-white solid (319 mg, 97%yield). MS (ES⁺) m/e=251. ¹H NMR (DMSO-d₆) δH 1.27 (12H, s), 3.88 (3H,s), 4.89 (2H, br s), 7.13 (1H, s), 7.64 (1H, s).

Example 8

4-tert-Butyl-N-[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-benzamide

[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine(319 mg, 1.28 mmol) was dissolved in dichloromethane (5 mL).Triethylamine (117 μL, 1.40 mmol) and 4-tert-butylbenzoyl chloride (274μL, 1.40 mmol) were added and the reaction was stirred at roomtemperature for 10 minutes. The crude mixture was absorbed onto silicaand purified by column chromatography to give the title compound as anoff-white solid (274 mg, 52% yield). MS (ES⁺) m/e=411. ¹H NMR (CDCl₃) δH1.36 (12H, s), 1.39 (9H, s), 4.10 (3H, s), 7.55 (2H, d), 7.86 (2H, d),8.28 (1H, s), 8.36 (1H, br s), 9.07 (1H, s).

Example 9

4-tert-Butyl-N-[2-methoxy-5-(2-methylsulfanyl-pyrimidin-4-yl)-pyridin-3-yl]-benzamide

4-tert-Butyl-N-[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-benzamide(274 mg, 0.67 mmol), 4-chloro-2-thiomethylpyrimidine (116 μL, 1.00 mmol)and Pd(Pph₃)₄ (77 mg, 10 mol %) were dissolved in toluene (10 mL) andEtOH (2 mL). Na₂CO₃ (488 mg, 4.61 mmol) in water (4 mL) was added andthe reaction mixture was heated to reflux for 2 hours. After coolingdown to room temperature, the reaction mixture was diluted with waterand extracted with EtOAc (×3). The combined organic extracts were driedover MgSO₄, filtered and concentrated in vacuo. The residue was absorbedonto silica and purified by column chromatography to give the titlecompound as a yellow solid (120 mg, 44% yield). MS (ES⁺) m/e=409. ¹H NMR(CDCl₃) δH 1.40 (9H, s), 2.69 (3H, s), 4.17 (3H, s), 7.41 (1H, d), 7.57(2H, d), 8.45 (1H, br s), 8.56 (1H, d), 8.76 (1H, d), 9.46 (1H, d).

Example 10

4-tert-Butyl-N-[5-(2-methylsulfanyl-pyrimidin-4-yl)-2-oxo-1,2-dihydro-pyridin-3-yl]-benzamideII-4

4-tert-Butyl-N-[2-methoxy-5-(2-methylsulfanyl-pyrimidin-4-yl)-pyridin-3-yl]-benzamide(120 mg, 0.29 mmol) was dissolved in 1,4-dioxane (6 mL) and water (1.2mL). Concentrated Hcl (600 μL) was added and the reaction mixture washeated to reflux for 30 minutes. The reaction mixture was cooled down toroom temperature and water was added. The obtained precipitate wasisolated by filtration and dried under vacuum. The crude solid waspurified by flash chromatography to give the title compound as a fawnsolid (29 mg, 25% yield). MS (ES⁺) m/e=395. ¹H NMR (DMSO-d₆) δH 1.33(9H, s), 2.58 (3H, s), 7.59 (2H, d), 7.64 (1H, d), 7.88 (2H, d), 8.21(1H, s), 8.58 (1H, d), 9.11 (1H, s), 9.30 (1H, s), 12.72 (1H, br s).

Example 11

N-(1,2-dihydro-5-(2-(methylamino)pyrimidin-4-yl)-2-oxopyridin-3-yl)-4-(piperidin-1-yl)benzamideII-40

4-Bromo-N-(2-methoxy-5-(2-(methylamino)pyrimidin-4-yl)pyridin-3-yl)benzamide(50 mg, 0.121 mmol) was placed in a microwave tube equipped with astirrer bar. NMP (1.5 mL) was added, followed by piperidine (1.5 mL).The reaction vessel was heated at 160° C. for 2 hours in a microwave.After cooling, the solvent and excess piperidine were removed in vacuo.The crude compound was recrystallized from methanol to give the titlecompound as a white solid (22 mg, 45% yield).). MS (ES⁺) m/e=405. ¹H NMR(DMSO-d₆) δH 1.54-1.61 (6H, m), 2.85 (3H, br s), 3.28-3.36 (4H, m),6.95-7.12 (4H, m), 7.77 (2H, d), 8.00 (1H, s), 8.27 (1H, d), 9.02 (1H,br s), 9.09 (1H, s), 12.53 (1H, br s).

A variety of other compounds of Formula II have been prepared by methodssubstantially similar to those described herein. The characterizationdata for these compounds is summarized in Table II-A below and includesHPLC, LC/MS (observed) and ¹H NMR data.

¹H NMR data is summarized in Table II-A below wherein ¹H NMR data wasobtained at 400 Mhz in deuterated DMSO, unless otherwise indicated, andwas found to be consistent with structure. Compound numbers correspondto the compound numbers listed in Table 1. TABLE II-A CharacterizationData for Selected Compounds of Formula I Compound No II- M+1(obs)Rt(min) ¹H-NMR 1 321 9.5 5.26(2H, s), 7.28-7.51(11H, m), 7.85(1H, s),8.56(1H, s), 12.49(1H br s) 2 291 8.9 7.33-7.62(9H, m), 7.95(2H, m),8.71(1H, s), 9.36(1H, s), 12.34(1H, br s) 3 See, Example 6 4 See,Example 10 5 432 9.8 1.38(9H, s), 3.80-4.14(8H, br m), 6.85(1H, d),7.16(1H, d), 7.54(2H, d), 7.60(1H, t), 7.88(2H, d), 7.94(1H, br s),8.94(2H, br s), 9.01(1H, s), 9.28(1H, s), 12.47(1H, br d) 6 391 10.41.33(9H, s), 3.11(6H, s), 6.62(1H, br d), 7.00(1H, d), 7.58(3H, d),7.88(3H, d), 9.05(1H, br s), 9.27(1H, br s), 12.45(1H, br s) 7 377 9.81.33(9H, s), 2.91(3H, s), 6.94(1H, br d), 7.36-7.46(1H, m),7.53-7.69(3H, m), 7.88(3H, d), 8.90(1H, br s), 9.36(1H, br s), 12.56(1H,br s) 8 365 — (CDCl₃) 1.25(9H, s), 7.05(2H, m), 7.25(1H, s), 7.45(2H,d), 7.50(2H, d), 7.85(2H, d), 8.95(1H, s), 9.05(1H br, s) 9 391 —(MeOH-d₄) 1.35(1H, m), 1.47(4H, m), 1.80(1H, m), 1.90(4H, m), 2.62(1H,m), 7.15(2H, m), 7.40(3H, m), 7.55(2H, m), 7.90(2H, d), 8.85(1H, s) 10362 — 1.31(9H, s), 6.80(2H, m), 7.30(3H, m), 7.55(3H, m), 7.85(2H, m),6.65(1H, m), 9.30(1H, br s) 11 372 — 1.33(9H, s), 7.58(2H, m), 7.75(2H,m), 7.80(1H, d), 7.85(4H, m), 8.70(1H, s), 9.40(1H, br s) 12 353 —1.33(9H, s), 7.05(2H, m), 7.18(1H, m), 7.30(1H, m), 7.55(2H, m),7.60(1H, s), 7.83(2H, m), 8.50(1H, m), 9.45(1H, br s) 13 392 — 1.30(9H,s), 7.55(3H, m), 7.80(1H, br s), 7.90(4H, m), 8.30(2H, m), 8.80(1H, s),9.30(1H, s) 14 378 9.5 1.33(9H, s), 2.91(3H, br s), 7.14(1H, br s),7.59(2H, d), 7.88(2H, d), 8.17(1H, br s), 8.29(1H, d), 9.07(1H, br s),9.30(1H, s), 12.70(1H, br s) 15 351 — 1.33(9H, s), 3.85(3H, s), 7.40(1H,s), 7.60(2H, d), 7.65(1H, s), 7.85(2H, d), 8.00(1H, s), 8.50(1H, s),9.30(1H, br s) 16 426 — 1.32(9H, s), 7.33(1H, s), 7.57(2H, d), 7.65(1H,m), 7.78(2H, d), 7.90(4H, m), 8.75(1H, s), 9.30(1H, s) 17 378 9.2 (80°C.) 3.01(3H, s), 6.90(1H, s), 7.60(2H, d), 7.88(2H, d), 8.04(1H, d),8.34(1H, s), 8.81(1H, s), 9.22(1H, s), 12.58(1H, br s) 18 392 9.61.32(9H, s), 3.30(6H, s), 7.16(1H, s), 7.59(2H, d), 7.90(2H, d),8.18(1H, d), 8.73(1H, s), 8.80(1H, s), 9.40(1H, s), 12.99(1H, br s) 19520 10.1 1.19(3H, t), 1.32(9H, s), 1.46(2H, m), 1.96(2H, m),2.85-3.10(2H, m), 3.92-4.10(6H, m), 7.33(1H, br s), 7.58(2H, d),7.88(2H, d), 8.32(3H, m), 9.06-9.16(1H, m), 9.29(1H, s), 12.87(1H, s) 20421 9.4 1.32(9H, s), 2.62(3H, m), 3.19(2H, m), 3.74(2H, m), 7.32(1H, brs), 7.59(2H, d), 7.89(2H, d), 8.17(1H, vbr s), 8.37(1H, br s), 8.87(2H,vbr s), 9.08(1H, s), 9.33(1H, s), 12.87(1H, br s) 21 392 10.0 1.33(9H,s), 3.23(6H, s), 7.16(1H, br s), 7.58(2H, d), 7.88(2H, d), 8.19(1H, brs), 8.34(1H, d), 9.12(1H, s), 9.29(1H, s), 12.70(1H, br s) 22 392 9.81.21(3H, t), 1.32(9H, s), 3.50(3H, br m), 7.31(1H, br d), 7.58(2H, d),7.88(2H, d), 8.30(1H, s), 8.31(1H, br s), 9.08(1H, s), 9.31(1H, s),12.86(1H, br s) 23 406 10.1 1.24(6H, d), 1.33(9H, s), 4.12(2H, br m),7.24(1H, br s), 7.58(2H, d), 7.88(2H, d), 8.26(1H, br s), 8.29(1H, d),9.06(1H, s), 9.31(1H, s), 12.82(1H, br s) 24 454 10.3 1.32(9H, s),4.66(2H, br s), 7.22-7.35(4H, m), 7.49(1H, br s), 7.59(2H, d), 7.89(2H,d), 8.28(1H, br s), 8.32(1H, br s), 9.10(1H, br s), 9.31(1H, s),12.84(1H, br s) 25 433 9.7 1.33(9H, s), 3.22(4H, br m), 4.04(4H, br m),7.19(1H, d), 7.59(2H, d), 7.88(2H, d), 8.14(1H, br d), 8.43(1H, d),8.93(1H, br s), 9.04(1H, s), 9.31(1H, s), 12.71(1H, br d) 26 348 9.67.45(1H, t), 7.58(2H, d), 7.85(2H, d), 7.94-8.04(3H, m), 8.65(1H, d),9.04(1H, s), 9.31(1H, s). 27 519 10.4 1.20(3H, t), 1.32(9H, s),1.96-2.05(2H, m), 2.95-3.12(2H, m), 3.30-3.36(2H, m), 3.90-4.06(5H,m+q), 6.37(1H, d), 6.52-6.58(1H, m), 6.85(1H, d), 7.40(1H, t), 7.57(2H,d), 7.76-7.84(1H, m), 7.84(1H, d), 9.07(1H, s), 9.20(1H, s). 28 448 9.51.32(9H, s), 1.76-7.82(2H, m), 2.07-2.20(2H, m), 3.07(2H, br m),3.33-3.39(2H, m), 4.10(1H, m), 7.29(1H, br s), 7.49(2H, d), 7.88(2H, d),8.27(1H, br s), 8.34(1H, s), 9.01-9.23(1H, br m), 12.82(1H, br s) 29 4489.5 1.32(9H, s), 1.61-2.07(4H, m), 2.82-2.99(2H, br m), 3.19(1H, m),3.39(1H, m), 4.21(1H, m), 7.23(1H, br s), 7.59(2H, d), 7.89(2H, d),8.08-8.28(2H, br m), 8.35(1H, s), 9.06(1H, s), 12.79(1H, br s) 30 4339.5 1.32(9H, s), 2.07(1H, m), 2.25(1H, m), 3.28(2H, m), 3.37(1H, m),3.47(1H, m), 4.55(1H, m), 7.25(1H, s), 7.59(2H, d), 7.88(2H, d),8.16(1H, s), 8.35(1H, d), 9.08(1H, s), 9.14-9.26(1H, br m), 12.76(1H, brs) 31 433 9.5 1.32(9H, s), 2.09(1H, m), 2.27(1H, m), 3.27(2H, m),3.39(1H, m), 3.45(1H, m), 4.49(1H, m), 7.28(1H, s), 7.61(2H, d),7.88(2H, d), 8.19(1H, s), 8.36(1H, d), 9.12(1H, s), 9.14-9.35(1H, br m),12.80(1H, br s) 32 447 9.8 1.22-1.30(2H, m), 1.33(9H, s), 1.86-1.95(2H,m), 2.51-2.60(2H, m), 2.91-2.97(2H, m), 3.75-3.85(1H, m), 6.35(1H, d),6.47(1H, d), 6.83(1H, d), 7.36(1H, t), 7.59(2H, d), 7.80(1H, s),7.85(2H, d), 9.02(1H, s), 9.22(1H, s). 33 433 9.5 1.32(9H, s), 3.23(4H,s), 4.05(4H, s), 7.36(1H, s), 7.59(2H, d), 7.89(2H, d), 8.22(1H, s),8.71(1H, s), 8.96(1H, s), 9.35(1H, s), 9.38(1H, br s), 12.86(1H, br s)34 349 9.4 1.32(9H, s), 7.59(2H, d), 7.88(2H, d), 7.98(1H, d), 8.22(1H,s), 8.76(1H, d), 9.17(2H, d), 9.30(1H, s), 12.71(1H, br s) 35 420 9.11.35(9H, s), 2.65(3H, s), 3.16-3.25(2H, m), 3.63-3.70(2H, m), 7.03(1H,d), 7.60(2H, d), 7.90(2H, d), 8.80-8.95(2H, m), 9.00(1H, s), 9.32(1H, s)36 409 10.1 1.33(9H, s), 2.37(3H, s), 2.55(3H, s), 7.55(2H, d), 7.69(1H,s), 7.85(2H, d), 8.48(1H, s), 8.78(1H, s), 9.25(1H, s). 37 311 —5.17(2H, s), 7.35(7H, m), 7.85(2H, br s), 8.10(1H, s), 8.37(1H, br s) 38421 8.7 1.32(9H, s), 2.58-2.60(3H, m), 3.13-3.15(2H, m), 3.75-3.76(2H,m), 6.94(1H, br s), 7.59(2H, d), 7.89(2H, d), 8.11(1H, br s), 8.69(1H,s), 8.84(1H, s), 8.93(2H, br s), 9.36(1H, s), 12.85(1H, br s) 39 433 8.71.32(9H, s), 1.99(1H, m), 2.38(1H, m), 3.16(1H, m), 3.30(1H, m),3.37(1H, m), 3.52(1H, m), 4.64(1H, m), 6.93(1H, s), 7.61(2H, d),7.88(2H, d), 8.09(1H, br s), 8.69(1H, s), 8.85(1H, s), 9.33(2H, br s),9.36(1H, s), 12.82(1H, br s) 41 424 10.1 1.31(9H, s), 2.83(3H, s),6.49(1H, s), 7.46-7.61(3H, m), 7.81-7.98(3H, m), 8.90(1H, br s),9.27(1H, s), 12.48(1H, br s) 42 376 9.7 1.31(9H, s), 2.11(3H, s),4.95(2H), 6.41-6.51(2H, m), 6.89(1H, m), 7.05(1H, s)), 7.58(2H, m)7.85(2H, m), 8.32(1H, s), 9.25(1H) 43 390 10.2 1.36(9H, s), 2.15(3H, s),2.67(3H, m), 5.55(1H, m), 6.36-6.51(2H, m), 6.97(1H, m), 7.08(1H, s)),7.58(2H, m) 7.85(2H, m), 8.35(1H, s), 9.25(1H) 44 391 10.5 1.31(9H, s),2.22(3H, s), 3.75(3H, s), 6.78-6.89(2H, m), 7.18-7.22(2H, m, 7.58(2H,m), 7.85(2H, m), 8.35(1H, s), 9.29(1H) 45 460 8.6 1.55-1.65(6H, m),1.94(1H, m), 2.24(1H, m), 3.11(1H, m), 3.27-3.29(2H, m), 3.29-3.35(4H,m), 3.44(1H, m), 4.53(1H, m), 6.82(1H, s), 7.02(2H, d), 7.77(2H, d),7.86-7.94(2H, m), 8.50(1H, s), 8.96-8.99(2H, m), 9.10(1H, s), 12.51(1H,br s) 46 405 8.9 1.50-1.60(6H, m), 2.84(3H, br s), 3.31-3.34(4H, m),6.75(1H, s), 7.02(2H, d), 7.39(1H, br s), 7.77(2H, d), 7.92(1H, br s),8.42(1H, s), 8.95(1H, s), 9.09(1H, s), 12.44(1H, br s) 47 404 9.51.55-1.65(6H, m), 3.30-3.37(4H, m), 2.83(3H, s), 6.33(1H, d),6.48-6.59(1H, br s), 6.84(1H, d), 7.00(2H, d), 7.43(1H, t),7.72-7.80(3H, m), 9.00(1H, s), 9.06(1H, s). 48 432 10.1 1.21(6H, d),1.55-1.63(6H, m), 3.30-3.38(4H, m), 3.99-4.09(1H, m), 6.33(1H, d),6.38(1H, d), 6.76(1H, d), 6.99(2H, d), 7.36(1H, t), 7.72-7.78(3H, m),8.93(1H, s), 9.05(1H, s). 49 430 10.1 0.40-0.46(2H, m), 0.67-0.75(2H,m), 1.55-1.64(6H, m), 2.49-2.57(1H, m), 3.30-3.38(4H, m), 6.50(1H, d),6.80(1H, s), 6.91(1H, d), 7.00(1H, d), 7.49(1H, t), 7.71-7.79(3H, m),8.97(1H, s), 9.05(1H, s). 50 480 10.3 1.55-1.64(6H, m), 3.30-3.38(4H,m), 4.53(2H, d), 6.37(1H, d), 7.83(1H, d), 7.00(2H, d), 7.15-7.22(2H,m), 7.25-7.33(2H, m), 7.35-7.44(3H, m), 7.70-7.77(3H, m), 8.96(1H, s),9.05(1H, s) 51 447 8.7 1.53-1.64(6H, m), 2.30(3H, s), 2.63-2.70(2H, m),3.30-3.44(6H, m), 6.35(1H, d), 6.45-6.52(1H, m), 6.80(1H, d), 7.00(2H,d), 7.38(1H, t), 7.70-7.78(3H, m), 8.95(1H, s), 9.05(1H, s). 52 422 9.81.59(6H, br s), 2.54(3H, s), 3.23(4H, br s), 7.01(2H, d), 7.36(1H, brs), 7.71(2H, d), 8.33(1H, br s), 8.39(1H, br s), 8.84(1H, br s),9.39(1H, br s) 53 432 10.2 1.30(6H, d), 1.60(6H, br s), 2.46(4H, br s),3.10(1H, m), 3.31(3H, s), 7.02(2H, d), 7.60(1H, s), 7.77(2H, d),8.10(1H, br d), 9.11(2H, br s d), 12.61(1H, br d) 54 377 10.3 1.34(9H,s), 3.85(3H, s), 6.91(1H, m), 7.10-7.16(2H, m), 7.36(1H, m), 7.58(3H,m), 7.89(2H, m), 8.71(1H, s), 9.30(1H) 55 362 9.7 1.31(9H, s), 2.55(3H,s), 7.41(1H, s), 7.56(2H, m), 7.89(3H, m), 8.40(1H, s), 8.70-8.78(2H,m), 9.35(1H) 56 405 9.1 1.62(6H, m), 2.90(3H, m), 6.34(1H, d), 7.04(2H,d), 7.38(1H, br m), 7.75(2H, d), 8.09(2H, m), 9.08(1H, s), 9.22(1H, s),12.35(1H, s) 57 420 9.7 1.79(3H, t), 2.01(6H, br s), 3.70(4H, br s),4.82(2H, m), 7.43(2H, d), 7.96(1H, m), 8.19(2H, d), 8.56(1H, br s),8.96(1H, m), 9.50(2H, d), 13.06(1H, br s) 58 462 9.4 1.53(6H, m),2.77(6H, m), 4.20-4.50(6H, m), 4.60-4.80(2H, m), 7.05(2H, m), 7.35(1H,m), 7.73(1H, m), 7.99(1H, m), 8.27(1H, m), 9.05(2H, m), 9.32(1H, br s),9.93(1H, br s), 12.91(1H, br s) 59 435 8.6 1.55-1.65(6H, m),3.33-3.40(6H, m), 3.54(2H, m), 4.58(1H, br s), 6.90-7.02(4H, m),7.76(2H, d), 7.98(1H, s), 8.26(1H, s), 8.99(1H, s), 9.08(1H, s),12.50(1H, br s) 60 448 8.9 1.50-1.65(6H, m), 2.34(3H, s), 2.77-2.90(2H,m), 3.24-3.40(4H, m), 4.30-4.40(2H, m), 6.60(1H, m), 6.93-7.05(2H, m),7.26-7.35(1H, m), 7.64-7.80(3H, m), 7.89(1H, s), 8.97(1H, s), 9.10(1H,s). 61 476 9.7 1.56(6H, m), 2.46(3H, masked signal), 2.85(6H, m),3.20-3.60(6H, m), 3.97(2H, m), 6.98-7.11(2H, m), 7.73(2H, br s),8.04(1H, br s), 8.34(1H, br s), 9.07(2H, br s), 9.26(1H, br s), 12.6((brs) 62 392 9.6 1.30(9H, s), 2.20(3H, s), 2.80(3H, d), 6.91(1H, br d),7.55-7.61(3H, m), 7.85(2H, d), 8.16(1H, s), 8.75(1H, s), 9.26(1H, s) 63448 8.7 1.60(6H, m), 2.62(3H, s), 3.16(2H, m), 3.33(4H, m), 3.62(2H, m),7.01(1H, d), 7.10(1H, d), 7.16(1H, t), 7.77(2H, d), 8.04(1H, m),8.33(1H, d), 8.58(2H, m), 9.06-9.09(2H, m), 12.6(1H, d) 64 322 7.62.82-2.89(3H, m), 6.99(1H, d), 7.11(1H, d), 7.53-7.67(3H, m), 7.94(2H,d), 8.05(1H, s), 8.27(1H, d), 9.04(1H, s), 9.35(1H, s), 12.58(1H, d). 65462 9.1 1.59(6H, m), 2.32(3H, s), 2.67(3H, s), 3.18(2H, m),3.35-3.60(4H, m), 3.78(2H, m), 7.00-7.10(3H, m), 7.76(2H, d), 8.03(1H,s), 8.33(1H, d), 9.07(2H, m) 66 433 9.8 1.21(3H, t), 1.59(6H, m),2.54(2H, m), 2.85(3H, s), 3.39(4H, br m), 6.82(1H, s), 7.01(2H, d),7.75(2H, d), 8.09(1H, s), 8.95(1H, s) 67 426 8.8 2.86(3H, br ss),7.01(1H, d), 7.12(1H, d), 7.60(2H, dd), 7.66-7.76(1H, m), 7.79(2H, d),7.88(2H, d), 8.06-8.12(3H, m), 8.28(1H, d), 9.05(1H, s), 9.55(1H, s),12.60(1H, s) 68 376 10.0 1.35(9H, s), 2.86(3H, s), 6.95(1H, m), 7.18(2H,m), 7.39(1H, m), 7.54(1H, s), 7.61(2H, d), 7.92(2H, d), 8.72(1H, s),9.31(1H, s) 69 403 9.7 1.58(6H, s), 2.71(3H, s), 3.36(4H, m), 6.45(1H,m), 6.65-6.72(2H, m), 6.98(2H, d), 7.11(1H, t), 7.37(1H, s), 7.75(2H,d), 8.67(1H, s) 70 434 9.0 1.53-1.62(6H, m), 3.30-3.42(4+2H, 2xm),3.51-3.60(2H, m), 4.72(1H, t), 6.38(1H, d), 6.53(1H, t), 6.80(1H, d),6.99(2H, d), 7.37(1H, t), 7.72-7.78(3H, m), 8.92(1H, s), 9.06(1H, s). 71448 9.6 1.54-1.65(6H, m), 3.27(3H, s), 3.30-3.37(4H, m), 4.46-4.55(4H,m), 6.2(1H, d), 6.63(1H, t), 6.85(1H, d), 7.01(2H, d), 7.41(1H, t),7.72-7.82(3H, m), 8.99(1H, s), 9.06(1H, s) 72 403 — (CDCl₃) 1.7-1.2(6H,m), 1.85(4H, m), 2.55(1H, m), 3.80(3H, s), 6.90(2H, d), 7.15(2H, m),7.30(2H, d), 7.40(2H, d), 7.85(2H, d), 8.95(1H, br s), 9.05(1H, br s) 73396 10.2 1.3(9H, s), 2.3(3H, s), 7.3(1H, d), 7.4(1H, s), 7.6(2H, d),7.8(1H, d), 7.9(2H, d), 8.6(1H, s) 74 389 9.1 1.6(6H, s), 3.4(4H, m),7.0(2H, br m), 7.2(1H, br m), 7.4-7.6(4H, m), 7.8(2H, d), 8.7(1H, s) 75446 9.1 1.6(6H, s), 2.6(3H, s), 3.1(2H, m), 3.3(4H, m), 3.4(2H, m),6.6(1H, m), 6.8(2H, m), 7.0(2H, m), 7.2(1H, t), 7.4(1H, s), 7.8(2H, m),8.6(1H, s), 9.1(1H, s) 76 449 8.6 1.59(6H, br s), 2.49(5H, br s),3.33(4H, br s), 4.53(2H, br s), 7.00(2H, br d), 7.63(1H, br s), 7.75(2H,br s), 8.17(1H, br s), 8.57(1H, br s), 9.08(2H, br d) 77 406 6.32.85(3H, s), 3.17-3.20(4H, m), 3.44-3.50(4H, m), 6.97(1H, d),7.05-7.12(3H, m), 7.85(2H, d), 8.01(1H, s), 8.27(1H, d), 9.02(1H, bs),9.15(1H, s). 78 448 7.7 1.01(6H, d), 2.53-2.59(4H, m), 2.66-2.69(1H, m),2.85(3H, bs), 3.26-3.36(4H, m), 6.97(1H, d), 7.03(2H, d), 7.09(1H, d),7.78(2H, d), 8.00(1H, s), 8.27(1H, d), 9.03(1H, s), 9.10(1H, s),12.51(1H, br s). 79 478 7.8 1.63-1.75(2H, m), 2.30-2.41(2H, m),2.82-2.90(4H, m), 3.22(3H, s), 3.28-3.39(6H, m), 6.94-7.12(4H, m),7.79(2H, d), 8.00(1H, s), 8.27(1H, d), 9.03(1H, s), 9.11(1H, s),12.53(1H, d). 80 474 7.9 1.66-1.73(4H, m), 1.89-2.09(4H, m),2.31-2.54(4H, m), 2.57-2.68(2H, m), 2.88(3H, bs), 3.11-3.19(1H, m),3.39-3.48(1H, m), 3.91-3.99(1H, m), 6.66(2H, d), 6.97(1H, d), 7.10(1H,d), 7.77(2H, d), 7.99(1H, s), 8.27(1H, d), 9.03(2H, s), 12.49(1H, bs).81 448 7.1 2.05(3H, s), 2.85(3H, s), 3.28-3.40(4H, m), 3.56-3.61(4H, m),6.97(1H, d), 7.02-7.11(3H, m), 7.81(2H, d), 8.01(1H, s), 8.26(1H, d),9.02(1H, s), 9.12(1H, s), 12.52(1H, br s). 82 386 6.5 1.02(9H, s),2.82(3H, s), 3.35-3.39(8H, m), 6.90(1H, m), 7.05(1H, m), 7.86(2H, m),8.24(1H, m), 8.68(1H, m), 12.38(1H, br s) 83 379 — 1.31(9H, s), 2.05(2H,m), 2.35(2H, m), 2.72(2H, m), 6.17(1H, s), 7.55(2H, m), 7.60(1H, m),7.88(2H, m), 8.65(1H, s), 9.25(1H, br s) 84 382 — — 85 392 — (CDCl₃)1.70-1.50(6H, m), 2.05(2H, m), 2.40(2H, m), 2.60(2H, m), 3.25(4H, m),6.35(1H, s), 6.90(2H, m), 7.30(1H, s), 7.80(2H, m), 8.90(2H, d) 86 407 —1.60(6H, s), 1.80(4H, m), 2.45(4H, m), 3.35(4H, m), 6.35(1H, s),7.00(2H, m), 7.25(1H, m), 7.75(2H, m), 8.70(1H, s), 9.10(1H, s) 87 378 —(CDCl₃) 1.50-1.70(6H, m), 2.50(2H, m), 2.90(2H, m), 3.30(4H, m), 6.43(s,1H), 6.85(2H, m), 7.35(1H, s), 7.80(2H, m), 8.90(2H, d) 88 365 — (CDCl₃)1.25(9H, s), 7.05(2H, m), 7.25(1H, s), 7.45(2H, d), 7.50(2H, d),7.85(2H, d), 8.95(1H, s), 9.05(1H, br s) 89 394 — 1.60(8H, m), 1.85(3H,m), 2.20(2H, m), 3.25(4H, m), 4.30(1H, br s), 6.05(1H, s), 6.85(2H, m),7.00(1H, s), 7.75(2H, m), 8.80(1H, m), 8.90(1H, m) 90 364. — — 91 496 —— 92 406 — — 93 433 9.6 1.21(3H, t), 1.60(6H, m), 2.54(2H, q), 2.87(3H,s), 3.3(4 masked protons), 6.17(1H, s), 7.02(2H, d), 7.77(2H, d),8.07(1H, s), 9.21(1H, s) 94 400 9.5 1.60(6H, m), 3.3(4 masked protons),7.02(2H, d), 7.70(1H, d), 7.77(2H, d), 8.09(1H, d), 8.39(1H, s),8.84(1H, d), 9.13(1H, d) 95 461 9.4 1.52-1.62(6H, m), 2.30(3H, s),2.70(2H, t), 3.05(3H, s), 3.24-3.36(4H, m), 3.61(2H, t), 6.51(1H, d),6.90(1H, d), 6.97(2H, d), 7.47(1H, t), 7.70(2H, d), 7.85(1H, s),9.03(1H, s), 9.05(1H, s) 96 503 9.3 0.93(6H, t), 1.55-1.60(6H, m),1.62-1.71(2H, m), 2.38-2.54(6H, m), 3.25-3.37(6H, m), 6.32(1H, d),6.57-6.63(1H, m), 6.80(1H, d), 7.00(2H, d), 7.37(1H, t), 7.71-7.80(3H,m), 8.95(1H, s), 9.03(1H, s) 97 428 9.2 2.88(3H, br s), 5.21(2H, s),7.09(1H, d), 7.17(2H, d), 7.30-7.48(5H, m), 7.92(2H, d), 8.12(1H, br s),8.28(1H, d), 9.03(1H, br s), 9.25(1H, s), 12.65(1H, br s) 98 412 9.42.85(3H, br s), 4.04(2H, s), 6.97(1H, d), 7.09(1H, d), 7.16-7.34(5H, m),7.42(2H, d), 7.86(2H, d), 8.04(1H, s), 8.25(1H, d), 9.02(1H, br s),9.28(1H, br s) 99 400 9.2 1.59(6H, m), 3.3(4 masked protons), 7.02(2H,d), 7.76-7.78(3H, m), 8.54(1H, s), 8.70(1H, d), 8.94(1H, s), 9.07(1H, d)100 377 6.1 2.77(4H, t), 3.57(4H, t), 6.88(1H, d), 7.60(2H, d), 7.78(1H,d), 8.00(1H, dd), 8.57(2H, d), 8.68(1H, d), 8.73(1H, d) 101 475 9.11.56-1.63(6H, m), 1.82(3H, s), 3.22-3.29(2H, m), 3.30-3.37(6H, m),6.36(1H, d), 6.63(1H, t), 6.99(2H, d), 7.41(1H, t), 7.73(2H, d),7.81(1H, s), 7.95(1H, t), 9.00(1H, s), 9.07(1H, s) 102 413 9.5 1.60(6H,br s), 3.34(4H, br s), 6.60(1H, d), 7.03(3H, t), 7.08(1H, t), 7.14(1H,d), 7.16(1H, d), 7.36(1H, d), 7.77(2H, d), 8.79(1H, d) 103 503 9.70.91(6H, m), 1.59(6H, m), 2.40-2.60(6H, m), 3.04(3H, s), 3.30-3.45(4H,m), 3.65(2H, m), 6.48(1H, m), 6.91(1H, m), 7.01(2H, d), 7.44(1H, m),7.75-7.781(3H, m), 9.03(2H, d), 12.30(1H, br s) 104 487 9.7 1.60(6H, m),1.87-1.91(2H, m), 2.02(2H, m), 3.15(2H, m), 3.28-3.30(4H, m),3.43-3.46(2H, m), 3.53-3.56(4H, m), 6.45(1H, d), 6.91(1H, br s),6.97-7.10(2H, m), 7.49(1H, m), 7.75-7.81(3H, m), 9.07-9.12(2H, m),9.51(1H, br s), 12.35(1H, m) 105 487 9.2 1.29-1.38(2H, m), 1.60(6H, m),1.91-2.03(4H, m), 2.90-2.93(2H, m), 3.24-3.25(2H, m), 3.30-3.34(5H, m),6.43(1H, d), 6.901(1H, d), 6.97-7.03(2H, m), 7.44(1H, m), 7.75-7.78(3H,m), 8.15(1H, d), 8.49(1H, d), 9.06-9.08(2H, m). 12.48(1H, br s) 106 4439.3 1.60(6H, m), 2.84-2.87(2H, m), 3.30-3.50(4H, m), 3.56-3.60(2H, m),6.45(1H, d), 6.92(1H, d), 7.01-7.05(3H, m), 7.48(1H, m), 7.76(2H, m),7.81(1H, d), 9.00(1H, d), 9.07(1H, s), 12.30(1H, s) 107 394 6.01.78-1.86(2H, m), 2.65-2.70(2H, m), 2.85-2.91(3H, m), 3.18(1.4H, t),3.30(0.6H, t), 6.67(2H, d), 7.06(1H, d), 7.72(2H, d), 8.03-8.09(1H, m),8.28(1H, d), 9.01(1H, s), 9.02-9.06(1H, m) 108 476 9.6 0.85-0.95(6H, m),1.51-1.62(6H, m), 1.65-1.77(1H, m), 2.82-2.90(1H, m), 3.24-3.35(4H, m),4.06-4.15(1H, m), 4.25-4.33(1H, m), 6.68(1H, d), 7.00(2H, d), 7.31(1H,d), 7.66-7.76(3H, m), 7.87(1H, s), 9.02(1H, s), 9.06(1H, s) 109 413 10.01.60(6H, br s), 3.25(4H, br s), 6.52(1H, d), 7.01-7.10(4H, m), 7.36(2H,d), 7.64(1H, d), 7.75(2H, d), 8.65(1H, d) 110 482 9.9 1.60(6H, br s),3.35(4H, br s), 7.02(2H, d), 7.50(1H, s), 7.78(2H, d), 7.83(1H, s),8.41(1H, s), 8.47(1H, br s), 9.01(1H, br s) 111 433 9.9 1.65-1.77(6H,m), 2.65(6H, s), 3.40-3.50(4H, m), 6.84(1H, d), 7.06(1H, d), 7.14(2H,d), 7.36(1H, s), 7.66(1H, t), 7.85-7.90(3H, m), 9.07(1H, s), 9.18(1H, s)112 461 9.1 1.07(6H, s), 1.53-1.62(6H, m), 3.23-3.37(6H, 2xm), 6.43(1H,d), 6.47(1H, t), 6.80(1H, d), 6.99(2H, d), 7.37(1H, t), 7.72(2H, d),7.76(1H, s), 8.98 91H, s), 9.04(1H, s) 113 390 8.6 1.60(6H, br s),3.34(4H, br s), 6.08(1H, br d), 6.38(1H, d), 6.84(1H, s), 7.02(2H, d),7.72-7.77(3H, m), 8.01(1H, d), 8.95(1H, s) 114 405 9.1 1.60(6H, m),2.87(3H, s), 3.3(4 masked protons), 7.02(2H, d), 7.76(2H, d), 7.78(1H,s), 7.90(1H, d), 8.08(1H, s), 8.98(1H, d) 115 404 9.2 1.60(6H, s),2.47(3H, s), 3.34(4H, s), 6.57(1H, s), 6.68(1H, d), 7.02(2H, d),7.59(1H, s), 7.75(2H, d), 7.97(1H, d), 8.66(1H, s) 116 389 9.7 1.60(6H,s), 2.37(3H, s), 3.35(4H, s), 7.02(2H, d), 7.12(1H, d), 7.66(1H, s),7.76(2H, d), 7.89(1H, d), 8.85(1H, d), 9.12(1H, s) 117 458 10.51.46-1.54(2H, m), 1.57-1.60(8H, m), 1.68-1.70(2H, m), 1.96-2.02(2H, m),3.35(4H, m), 4.15(1H, m), 6.37(1H, m), 6.56(1H, m), 6.82(1H, d),7.02(2H, d), 7.41(1H, m), 7.75-7.80(3H, m), 8.98(1H, s), 9.07(1H, s),12.3(1H, s) 118 378 8.6 1.60(6H, s), 3.35(4H, s), 3.64(3H, s), 7.01(3H,m), 7.28(1H, s), 7.75(3H, m), 8.38(1H, d) 119 517 10.0 0.86(3H, d),0.94(3H, d), 1.45-1.55(2H, m), 1.52-1.64(6H, m), 1.65-1.75(1H, m),2.57(3H, d), 3.32-3.42(4H, m), 4.29-4.38(1H, m), 6.45(1H, d),6.65-6.74(1H, m), 6.81(1H, d), 7.00(2H, d), 7.40(1H, t), 7.72-.82(4H,m), 8.89(1H, s), 9.08(1H, s) 120 501 9.7 0.95-1.10(3H, m), 1.53-1.75(9H,m), 1.78-2.65(4H, m), 2.85-3.18(3H, m), 3.30-3.37(4H, m), 3.55-3.68(1H,m), 6.38(1H, d), 6.5-6.85(1H, m), 7.00(2H, d), 7.37(1H, t),7.69-7.78(3H, m), 8.93(1H, s), 9.04(1H, s) 121 405 8.9 1.60(6H, s),3.34(4H, s), 4.60(2H, s), 7.02(2H, d), 7.34(1H, d), 7.63(1H, d),7.76(2H, d), 7.82(1H, t), 7.93(1H, d), 9.02(1H, s) 122 348 8.3 2.87(3H,br s), 6.98(1H, d), 7.35-7.47(4H, m), 7.57(1H, d), 7.65(2H, d), 8.02(1H,s), 8.27(1H, d), 9.20(1H, br s), 9.62(1H, s) 123 434 9.3 1.60(6H, m),2.80(6H, 2s), 3.3(4 masked protons), 6.05(1H, s), 6.41(1H, br s),6.89(1H, br s), 7.02(2H, d), 7.77(2H, d), 7.85(1H, s), 8.88(1H, s) 124432 9.2 1.54-1.63(6H, m), 2.85(3H, s), 3.25-3.40(4H, m), 7.00(2H, d),7.70-7.82(4H, m), 7.91(1H, t), 8.40(1H, s), 8.89(1H, s) 125 418 8.91.60(6H, s), 2.38(3H, s), 3.35(4H, s), 3.86(2H, s), 7.02(2H, d),7.32(1H, d), 7.66(1H, d), 7.79(2H, d), 7.82(1H, t), 7.96(1H, d),9.06(1H, d) 126 406 6.2 2.78-2.86(7H, m), 3.19-3.24(4H, m), 6.73(1H, s),7.02(2H, d), 7.34(1H, br s), 7.77(2H, d), 7.98(1H, br s), 8.41(1H, s),8.92(1H, br s), 9.16(1H, s) 127 501 10.1 1.55-1.60(10H, m), 1.70(3H, s),1.99(2H, m), 2.32(4H, m), 3.15(1H, m), 3.34(4H, m), 6.35(1H, d),6.63(1H, s), 6.84(1H, d), 7.02(2H, d), 7.40(1H, m), 7.76-7.78(3H, m),8.99(1H, s), 9.08(1H, s), 12.30(1H, s) 128 488 9.9 1.19-1.28(2H, m),1.60(6H, m), 1.67-1.70(4H, m), 1.88-1.91(2H, m), 3.23-3.37(5H, m),3.86-3.88(2H, m), 6.48(1H, s), 6.88(1H, m), 7.03(2H, d), 7.49(1H, m),7.60-7.80(4H, m), 8.96(1H, s), 9.09(1H, s), 12.40(1H, s) 129 447 9.11.16(3H, d), 1.53-1.63(6H, m), 2.55-2.73(2H, m), 3.25-3.40(4H, m),3.85-3.96(1H, m), 6.35(1H, d), 6.82(1H, d), 7.01(2H, d), 7.39(1H, t),7.70-7.80(3H, m), 8.97(1H, s) 130 419 9.4 — 131 478 7.3 — 132 476 9.80.93-0.98(6H, m), 1.60(6H, m), 1.78(1H, m), 2.94(1H, m), 3.34(4H, m),4.18(1H, m), 4.36(1H, m), 6.70(1H, d), 7.02(2H, d), 7.36(1H, d),7.73-7.89(3H, m), 7.90(1H, s), 9.04(1H, s), 9.09(1H, s) 133 490 10.10.96-0.99(9H, m), 1.60(6H, m), 2.96(1H, m), 3.32-3.34(4H, m), 4.13(1H,m), 4.64(1H, m), 6.75(1H, m), 7.02(2H, d), 7.38(1H, d), 7.71-7.78(3H,m), 7.90(1H, d), 9.06-9.08(2H, m) 134 448 7.7 1.10(2H, m), 1.48-1.78(5H,m), 2.40-2.47(2H, m), 2.85(3H, m), 2.89(2H, m), 4.10(2H, m), 6.31(1H,m), 6.52(NH), 6.85(1H, m), 7.09(2H, m), 7.42(1H, t), 7.81-7.91(3H, m),9.00(1H, s), 9.12(1H, s) 135 434 6.3 1.28(6H, d), 2.76(2H, t), 2.93(3H,s), 3.34-3.52(2H, m), 4.08(2H, d), 6.85(1H, s), 7.15(2H, d), 7.85(2H,d), 7.94(1H, br s), 8.59(1H, br s), 8.85(1H, br s), 9.21(1H, s),12.69(1H, br s) 136 474 7.6 1.84-2.20(8H, m), 2.93(3H, s), 3.06-3.52(6H,m), 3.57-3.68(1H, m), 3.78-3.86(1H, m), 4.18-4.28(1H, m), 6.77(2H, d),6.84(1H, br s), 7.83(2H, d), 7.93(1H, br s), 8.58(1H, br s), 8.87(1H, brs), 9.11(1H, s) 137 403 6.2 2.34-2.39(2H, m), 2.84(3H, s), 2.92(2H, t),3.30-3.42(2H, m), 6.40(1H, s), 6.74(1H, s), 7.60(2H, d), 7.89(2H, d),7.96-8.08(1H, m), 8.41(1H, s), 8.92(1H, br s), 9.38(1H, s) 138 449 7.42.38-2.42(4H, m), 2.67(6H, m), 2.81(3H, m), 4.14(2H, m), 6.35(1H, m),6.51(NH), 6.89(1H, m), 7.10(2H, m), 7.45(1H, t), 7.85-7.92(3H, m),8.98(1H, s), 9.11(1H, s) 139 406 6.5 (MeOD) 3.02(3H, s), 3.37(4H, t),3.60(4H, t), 7.16(2H, d), 7.78(1H, s), 7.95(2H, d), 7.97(1H, d),8.05(1H, s), 9.21(1H, d) 140 375 9.3 1.55-1.62(6H, m), 3.25-3.40(4H, m),6.98(2H, d), 7.16-7.22(1H, m), 7.71-7.80(4H, m), 7.95(1H, s),8.54-8.57(1H, m), 9.00(1H, s) 141 462 9.0 1.1(6H, m), 1.6(6H, s),3.2-3.4(6H, m), 7.0(3H, m), 7.7-7.8(2H, m), 7.8-7.9(2H, m), 8.0-8.1(1H,s), 9.0(1H, m), 9.1(1H, s) 142 449 6.8 1.21-1.36(2H, m), 1.72(3H, m),1.83(2H, m), 2.71-2.85(5H, m), 3.10(2H, m), 4.11(2H, m), 6.75(1H, s),7.10(2H, m), 7.39(NH), 7.91(2H, m), 8.45(1H, s), 8.95(1H, br s),9.22(1H, s) 143 449 7.2 1.18-1.30(2H, m), 1.69-1.85(5H, m), 2.68(2H, m),2.86(3H, m), 3.11(2H, m), 4.13(2H, m), 7.09(2H, m), 7.12(NH), 7.80(1H,m), 7.90(3H, m), 8.10(1H, m), 9.00(1H, s), 9.21(1H, s) 144 379 5.82.81-2.82(4H, m), 3.19-3.21(4H, m), 3.61(3H, s), 6.89(1H, s), 7.02(2H,d), 7.33(1H, s), 7.64(1H, s), 7.75(2H, d), 8.31(1H, s), 9.26(1H, s) 145474 8.0 — 146 420 6.7 1.74-1.82(2H, m), 2.63(2H, t), 2.82-2.90(5H, m),3.53(2H, t), 3.61(2H, t), 6.81(2H, d), 7.08-7.16(1H, m), 7.73(2H, d),7.80(1H, s), 7.86(1H, d), 8.09(1H, s), 9.00(1H, d) 147 421 7.61.85-2.08(4H, m), 2.88(3H, d), 3.09-3.18(1H, m), 3.20-3.28(1H, m),3.40-3.52(2H, m), 3.78-3.84(1H, m), 6.70(2H, d), 7.07-7.15(1H, m),7.76(2H, d), 7.80(1H, s), 7.87(1H, d), 8.09(1H, s), 9.00(1H, d) 148 4506.7 2.44(2H, t), 2.55(4H, t), 2.88(3H, d), 3.26-3.37(4H, m), 3.54(2H,t), 7.04(2H, d), 7.08-7.14(1H, m), 7.78(2H, d), 7.80(1H, s), 7.88(1H,d), 8.10(1H, s), 9.00(1H, d), 9.12(1H, s), 12.42(1H, br s) 149 478 9.11.04-1.13(3H, m), 1.50-1.62(6H, m), 3.78-3.85(1H, m), 3.63-3.83(1H, m),4.10-4.34(2H, 2xm), 6.54-6.61(1H, m), 7.01(2H, d), 7.21(1H, t), 7.66(1H,t), 7.71(2H, d), 8.01+8.11(1H, 2xs), 8.90(1H, s) 150 488 9.81.37-1.43(2H, m), 1.50-1.66(12H, m), 1.70-1.80(2H, m), 3.22-3.36(4H, m),4.18(2H, s), 6.60(1H, d), 7.01(2H, d), 7.20(1H, d), 7.65(1H, t),7.73(2H, d), 8.02(1H, s), 8.85(1H s) 151 462 9.6 0.96(3H, t),1.30-1.40(1H, m), 1.55-1.60(6H, m), 2.95-3.02(1H, m), 3.30-3.36(4H, m),4.10-4.27(2H, m), 6.70(1H, d), 7.01(2H, d), 7.32(1H, d), 7.70-7.78(4H,m), 7.86(1H, s), 9.01(1H, s) 152 490 10.1 0.86(3H, t), 0.95(3H, d),1.13-1.25(1H, m), 1.47-1.60(8H, m), 2.95-3.01(1H, m), 3.30-3.40(4H, m),4.10-4.20(1H, m), 3.38-3.45(1H, m), 6.70(1H, d), 7.00(2H, d), 7.33(1H,d), 7.70-7.85(3H, m), 7.90(1H, s), 9.05(1H, s) 153 435 7.0 1.41-1.52(2H,m), 1.96(2H, m), 2.13(1H, m), 2.89(3H, m), 3.01(4H, m), 3.97(2H, m),7.09(2H, m), 7.11(1H, s), 7.81(1H, s), 7.94(3H, m), 8.16(1H, s),9.00(1H, s), 9.24(1H, s) 154 469 8.2 1.65-1.75(4H, m), 1.94-2.09(4H, m),2.41-2.51(4H, m), 2.61-2.62(2H, m), 3.16(1H, m), 3.42(1H, m), 3.93(1H,m), 6.67(2H, d), 7.72(2H, d), 7.88(1H, d), 8.35(1H, m), 8.54(1H, d),8.76(1H, d), 8.97(1H, d), 9.42,(1H, d) 155 420 7.5 2.35-2.52(4H, m),2.62-2.86(3H, m), 2.87(3H, s), 3.28-3.48(4H, m), 7.07(2H, d), 7.80(1H,s), 7.82(2H, d), 7.89(1H, d), 8.10(1H, s), 9.00(1H, d), 9.14(1H, s),12.45(1H, d) 156 449 7.8 1.12-1.24(2H, m), 1.38(2H, q), 1.56-1.69(1H,m), 1.74(2H, d), 2.80(2H, t), 2.87(3H, s), 3.46(2H, t), 3.91(2H, d),7.02(2H, d), 7.08-7.14(1H, m), 7.76(2H, d), 7.80(1H, s), 7.88(1H, d),8.09(1H, s), 9.00(1H, d) 157 434 7.7 1.15-1.26(2H, m), 1.75(2H, m),1.78(1H, m), 2.85(3H, m), 2.98(2H, m), 3.40(2H, m), 3.89(2H, m),6.32(1H, m), 6.55(NH), 6.89(1H, m), 7.09(2H, m), 7.42(1H, m), 7.85(1H,s), 7.91(2H, m), 9.00(1H, s), 9.21(1H, s) 158 450 6.8 2.45(4H, m).2.71(2H, m), 2.81(4H, m), 2.89(3H, m), 4.18(2H, m), 7.08-7.12(3H, m),7.80(1H, s). 7.91(3H, m), 8.10(1H, s), 8.97(1H, s), 9.25(1H, s) 159 4049.0 1.55-1.63(6H, m), 2.72(3H, s), 3.25-3.40(4H, m), 6.97(1H, s),7.01(2H, d), 7.51(1H, s), 7.75(2H, d), 7.86(1H, s), 7.95(1H, s),8.51(1H, s) 160 430 79 2.8-3.0(7H, m), 3.1(4H, m), 6.7(1H, s), 7.0(2H,m), 7.1-7.2(1H, m), 7.2-7.3(1H, s), 7.7-7.8(2H, m), 7.9(1H, m), 9.0(1H,m), 9.1(1H, s) 161 401 7.2 2.8-2.9(4H, m), 3.2-3.3(4H, m), 7.0(2H, m),7.7(1H, m), 7.8(2H, m), 8.0-8.1(1H, m), 8.4(1H, s), 8.8(1H, m), 9.1(2H,m) 162 434 6.7 1.84-1.94(2H, m), 1.98-2.07(2H, m), 2.88(3H, s),3.02-3.10(2H, m), 3.30-3.42(2H, m), 3.48-3.54(2H, m), 3.56-3.64(2H, m),6.75(2H, d), 7.76(2H, d), 7.81(1H, s), 7.88(1H, d), 8.10(1H, s),9.00(1H, d) 163 420 6.4 1.47-1.58(2H, m), 1.90-1.98(2H, m), 2.88(3H, s),2.90-3.00(2H, m), 3.24-3.40(1H, m), 3.95-4.02(2H, m), 7.08(2H, d),7.81(2H, d), 7.82(1H, s), 7.90(1H, d), 8.11(1H, s), 9.02(1H, d) 164 4227.6 2.87(6H, s), 2.88(3H, s), 3.03(3H, s), 3.24-3.30(2H, m),3.75-3.81(2H, m), 6.90(2H, d), 7.81(1H, s), 7.82(2H, d), 7.89(1H, d),8.10(1H, s), 9.00(1H, d) 165 431 6.8 2.87(3H, s), 2.92(2H, t), 3.43(2H,t), 6.70(2H, d), 7.50(1H, s), 7.72(2H, d), 7.81(1H, s), 7.87(1H, d),8.09(1H, s), 8.97-9.01(2H, m), 9.03(1H, s), 12.43(1H, d) 166 434 7.92.14-2.26(2H, m), 2.88(6H, s), 2.90(3H, s), 3.30-3.64(3H, m),3.72-3.78(1H, m), 3.98-4.08(1H, m), 6.73(2H, d), 7.81(1H, s), 7.84(2H,d), 7.89(1H, d), 8.10(1H, s), 9.01(1H, d) 167 436 7.4 1.86-1.96(2H, m),2.78(6H, s), 2.88(3H, s), 3.01(3H, s), 3.07-3.14(2H, m), 3.49(2H, t),6.84(2H, d), 7.79(2H, d), 7.81(1H, s), 7.88(1H, d), 8.10(1H, s),9.00(1H, d) 168 445 7.1 2.04(2H, quintet), 2.87(3H, s), 3.06(2H, t),4.14(2H, t), 6.64(2H, d), 7.15(1H, s), 7.40(1H, s), 7.71(2H, d),7.81(1H, s), 7.86(1H, d), 8.09(2H, s), 9.00(1H, d), 9.02(1H, s) 169 4056.9 2.79-2.84(7H, m), 3.16-3.24(4H, m), 6.41(1H, m), 6.54(1H, s),6.66(1H, d), 7.02-7.03(2H, m), 7.74(2H, d), 7.91(1H, d), 8.56(1H, d),9.39(1H, d) 170 435 6.5 1.51(2H, m), 1.88(2H, m), 2.09(1H, m),2.78-2.86(5H, m), 3.21(2H, m), 3.95(2H, m), 6.78(1H, s), 7.11(2H, m).7.45(1H, br s), 7.93(2H, m), 8.45(1H, s), 8.96(1H, s), 9.23(1H, s) 171490 9.2 1.68-1.75(4H, m), 1.90-2.12(4H, m), 2.35-2.65(6H, m), 2.70(3H,s), 3.10-3.20(1H, m), 3.40-3.50(1H, m), 3.90-3.99(1H, m), 6.27(1H, d),6.45-6.55(2H, m), 6.70(2H, d), 7.43-7.61(2H, m), 7.75(2H, d), 8.68(1H,s) 172 473 7.9 1.70-1.80(4H, m), 1.98-2.07(4H, m), 2.401-2.49(2H, m),2.61-2.62(2H, m), 2.80(3H, s), 3.16-3.17(2H, m), 3.42-3.44(2H, m),3.95(1H, m), 6.52(1H, d), 6.58(1H, s), 6.66-6.70(3H, m), 7.62(1H, d),7.76(2H, d), 7.97(1H, d), 8.67(1H, d), 9.16(1H, s) 173 416 6.33.00-3.05(4H, m), 3.29-3.39(4H, m), 6.69(1H, d), 7.08(2H, d), 7.84(2H,d), 7.86-7.90(1H, m), 7.96(1H, d), 8.75(1H, s), 9.14-9.18(2H, m),12.08(1H, br s) 174 464 8.8 1.55-1.70(6H, m), 3.30-3.53(4+2H, m),4.13-4.25(2H, m), 4.62-4.72(1H, m), 6.71(1H, d), 7.03(2H, d), 7.33(1H,d), 7.70-7.80(3H, m), 7.88(1H, s), 9.00(1H, s), 9.07(1H, s) 175 488 8.41.21(3H, t), 1.71(4H, br s), 1.91-2.07(4H, m), 2.33-2.40(1H, m),2.61-2.68(4H, m), 3.12-3.19(1H, m), 3.35(3H, s), 3.38-3.46(1H, m),3.93-3.97(1H, m), 6.67(2H, d), 7.11-7.14(1H, m), 7.76(1H, s), 7.78(2H,d), 7.85(1H, d), 8.07(1H, s), 8.97(1H, d) 176 500 8.6 0.41(2H, br s),0.78(2H, br d), 1.71(3H, br s), 1.81-2.19(7H, br m), 2.65(2H, br s),3.16(1H, br s), 3.36(3H, s), 3.45(1H, br s), 3.87-3.97(1H, m), 6.68(2H,br d), 7.78(2H, br s), 7.88(1H, s), 7.92(1H, s), 8.21(1H, s), 9.00(1H,s), 9.06(1H, s) 177 463 7.1 1.41-1.58(6H, br m), 1.91(2H, br m),2.38(4H, m) 2.90(3H, m), 3.35(4H, m), 4.11(2H, m), 7.07-7.15(NH and 2H,m), 7.82(1H, s). 7.96(3H, m), 8.13(1H, s), 9.01(1H, s), 9.27(1H, s) 178473 7.5 1.91(4H, m), 2.04(4H, m), 2.50-2.51(2H, m), 2.76(3H, s),3.15-3.22(2H, m), 3.45-3.49(2H, m), 3.65(1H, m), 3.80(1H, m), 4.24(1H,m), 6.06(1H, m), 6.78(2H, d), 6.97(1H, m), 7.50(1H, m), 7.81(2H, d),7.93(1H, m), 7.97(1H, m), 8.67(1H, m), 9.12(1H, s), 10.02(1H, br s) 179497 9.0 1.65-1.75(4H, m), 1.85-2.05(6H, m), 2.50-2.60(3H, m), 2.75(3H,d), 3.08-3.19(1H, m), 3.35-3.45(2H, m), 3.85-3.92(1H, m), 6.27-6..34(1H,m), 6.63(2H, d), 6.75(1H, s), 6.94(1H, s), 7.09(1H, s), 7.48(1H, s),7.75(2H, d), 8.63(1H, s), 9.04(1H, s) 180 542 8.8 1.71(4H, br s),1.94-2.19(4H, m), 2.38-2.51(4H, m), 2.61-2.68(2H, m), 3.16-3.18(1H, m),3.44-3.47(1H, m), 3.92-3.95(1H, m), 4.20-4.32(2H, m), 6.67(2H, d),7.71(1H, br t), 7.76(2H, d), 7.83(1H, s), 7.98(1H, s), 8.21(1H, s),8.92(1H, s), 9.15 91H, s) 181 421 6.6 1.45(2H, m), 1.98(2H, m), 2.61(2H,m) 2.95(3H, m), 3.00(2H, m), 4.55(2H, m), 7.10-7.15(NH and 2H, m),7.86(1H, s). 7.95(3H, m), 8.15(1H, s), 9.02(1H, s), 9.28(1H, s) 182 4657.7 1.95(2H, m), 2.39(4H, m), 2.89(3H, m) 3.35(2H, m), 3.59(4H, m),4.12(2H, m), 7.08-7.14(3H, m), 7.80(1H, s). 7.89(3H, m), 8.10(1H, s),8.99(1H, s), 9.24(1H, s)

Example 12

2-Oxo-5-phenyl-1,2-dihydro-pyridine-3-carboxylic acid phenylamide III-1

To a solution of 2-Oxo-5-phenyl-1,2-dihydro-pyridine-3-carboxylic acid(44 g, 0.20 mmol) in tetrahydrofuran (5 mL) were successively addedaniline (20 μL, 0.23 mmol), hydroxybenzotriazole (30 mg, 0.23 mmol),dimethylaminopyridine (27 mg, 0.23 mmol) and EDC (43 mg, 0.23 mmol). Thereaction mixture was stirred at room temperature for 16 hours. Thesolvent was removed in vacuo and the residue was purified by silica gelchromatography eluting with DCM containing 10% of MeOH to afford thetitle compound as a white solid (20 mg, 34% yield). MS (ES⁺) 291. δH(DMSO-d₆) 7.2 (3H, m), 7.9 (1H, t), 8.5 (1H, d), 8.6 (2H, m), 9.3 (1H,s).

A variety of other compounds of Formula III have been prepared bymethods substantially similar to those described herein Example 12. Thecharacterization data for these compounds is summarized in Table III-Abelow and includes HPLC, LC/MS (observed) and ¹H NMR data.

¹H NMR data is summarized in Table III-A below wherein ¹H NMR data wasobtained at 400 Mhz in deuterated DMSO, unless otherwise indicated, andwas found to be consistent with structure. Compound numbers correspondto the compound numbers listed in Table 1. TABLE III-A CharacterizationData for Selected Compounds of Formula III Compound No III- M+1(obs)Rt(min) ¹H-NMR 2 305 8.6 4.56(2H, d), 7.28(1H, m), 7.34-7.37(5H, m),7.46(2H, t), 7.62(2H, d), 8.06(1H, s), 8.66(1H, d), 10.20(1H, br t),12.86(1H, br s). 3 306 7.4 4.51(2H, d), 7.20-7.40(5H, m), 7.60(2H, d),8.40(1H, m), 8.50-8.70(3H, m), 11.10(1H, br s). 4 334 9.2 1H NMR(DMSO)1.19-1.25(6H, m), 2.80-2.92(1H, m), 7.19-7.29(2H, m), 7.58-7.66(2H, m),7.70-7.76(2H, m), 8.35-8.40(1H, m), 8.58-8.65(2H, m), 8.78-8.83(1H, m),12.08(1H, br s), 13.22(1H, br s). 5 348 9.6 1.29(9H, s), 7.39(2H, d),7.63(2H, d), 7.73(2H, d), 8.39(1H, d), 8.61(2H, d), 8.81(1H, d),12.10(1H, br s), 13.24(1H, br s). 6 320 7.6 2.84(2H, t), 3.58(2H, q),7.18-7.34(5H, m), 7.65-7.69(2H, m), 8.29(1H, d), 8.57-8.61(2H, m),8.70(1H, d), 9.78(1H, br t), 13.0(1H, br s). 7 320 8.8 1.18(3H, t),2.59(2H, q), 7.21(2H, d), 7.62(2H, d), 7.73(2H, d), 8.39(1H, d),8.61(2H, d), 8.80(1H, d), 12.10(1H, br s), 13.20(1H, br s). 8 371 8.97.57(2H, d), 7.68-7.75(4H, m), 8.41(1H, d), 8.61(2H, d), 8.81(1H, d),12.20(1H, s), 13.30(1H, br s). 9 384 9.3 6.96-7.18(5H, m), 7.32-7.46(2H,m), 7.62-7.81(4H, m), 8.35-8.45(1H, m), 8.56-8.66(2H, m), 8.77-8.84(1H,m), 12.19(1H, br s). 10 334 9.2 1.22(6H, d), 2.83-2.96(1H, m),6.98-7.04(1H, m), 7.24-7.33(1H, m), 7.51-7.61(2H, m), 7.68-7.78(2H, m),8.35-8.40(1H, m), 8.59-8.64(2H, m), 8.78-8.84(1H, m), 12.02(1H, br s).11 322 — (300Mhz) 3.75(3H, s), 6.95(2H, d), 7.64(2H, d), 7.72(21H, d),8.36(1H, d), 8.61(2H, d), 8.80(1H, d), 11.92(1H, s) 12 322 — (300Mhz)3.77(3H, s), 6.7(1H, d), 7.16(1H, d), 7.27(1H, t), 7.47(1H, s), 7.72(2H,d), 8.39(1H, s), 8.60(2H, d), 8.79(1H, d), 12.20(1H, s), 13.0(1H, br s)13 336 — (300Mhz) 1.33(3H, d), 4.7(1H, q), 5.2(1H, br s), 7.13(1H, d),7.36(1H, t), 7.62(1H, d), 7.64(1H, s), 7.71(2H, d), 8.40(1H, d),8.61(2H, d), 8.80(1H, d), 12.23(1H, s), 13.2(1H, br s) 14 336 — (300Mhz)3.85(3H, s), 4.50(2H, d), 6.91(1H, t), 7.02(1H, d), 7.30-7.22(2H, m),7.67(2H, dd), 8.29(1H, d), 8.59(2H, d), 8.71(1H, d), 10.09(1H, t) 15 384— (300Mhz) 6.83-6.79(1H, m), 7.08-7.05(2H, m), 7.28-7.18(2H, m),7.47-7.39(3H, m), 7.59(1H, t), 7.70(2H, dd), 8.33(1H, d), 8.60(2H, dd),8.78(1H, d), 12.11(1H, br s), 13.24(1H, br s) 16 352 — (300Mhz) 3.76(3H,s), 3.79(3H, s), 6.95(1H, d), 7.20(1H, dd), 7.45(1H, d), 7.72(2H, dd),8.37(1H, d), 8.61(2H, d), 8.81(1H, d), 11.95(1H, br s) 17 334 — (300Mhz)1.84(2H, quint.), 2.64(2H, t), 3.34(2H, q), 7.31-7.15(5H, m), 7.94(2H,d), 8.39(1H, d), 8.68(2H, d), 8.78(1H, d), 9.70(1H, t), 13.16(1H, br s)18 410 — (300Mhz) 2.31(2H, q), 3.25(2H, t), 4.03(1H, t), 7.17(2H, t),7.35-7.28(8H, m), 7.67(2H, dd), 8.28(1H, d), 8.58(2H, dd), 8.67(1H, d),9.77(1H, t), 12.90(1H, br s) 19 396 — (300Mhz) 7.48(1H, d),7.79-7.55(8H, m), 7.89(1H, d), 8.23(1H, s), 8.40(1H, d), 8.60(2H, d),8.80(1H, d), 12.40(1H, br s), 13.0(1H, br s) 20 350 — (300Mhz) 2.82(2H,q), 3.53(2H, q), 3.79(3H, s), 6.87(1H, t), 6.96(1H, d), 7.23-7.16(2H,m), 7.67(2H, d), 8.27(1H, d), 8.59(2H, d), 8.69(1H, d), 9.70(1H, t),12.90(1H, br s) 21 334 — (300Mhz) 1.25(3H, d), 3.0(1H, sext.),3.55-3.49(2H, m), 7.34-7.18(5H, m), 7.66(2H, d), 8.26(1H, d), 8.58(2H,d), 8.68(1H, d), 9.74(1H, t), 12.86(1H, br s) 22 286 — (300Mhz)0.92-0.88(6H, m), 1.10(3H, d), 1.76(1H, sext.), 3.90(1H, sext.),7.67(2H, d), 8.27(1H, d), 8.59(2H, d), 8.70(1H, d), 9.73(1H, d),12.94(1H, br s) 23 382 — (300Mhz) 3.95(2H, s), 7.0(1H, d), 7.32-7.19(5H,m), 7.56(1H, s), 7.58(2H, d), 7.71(2H, d), 8.38(1H, d), 8.61(2H, d),8.79(1H, d), 12.10(1H, br s), 13.20(1H, br s) 24 256 — (300Mhz)0.55-0.49(2H, m), 0.79-0.70(2H, m), 2.90-2.84(1H, m), 7.67(2H, dd),8.27(1H, d), 8.59(2H, d), 8.68(1H, d), 9.68(1H, s), 12.98(1H, br s) 25313 — (300Mhz) 9.79(1H, s), 8.70(1H, d), 8.59(2H, d), 8.28(1H, d),7.67(2H, d), 3.48(2H, t), 2.79-2.69(6H, m), 1.80-1.60(4H, m) 26 328 —(300Mhz) 1.58-1.24(10H, m), 3.30(2H, s), 4.39(1H, s), 7.68(2H, d),8.28(1H, d), 8.59(2H, dd), 8.71(1H, d), 9.84(1H, t), 12.89(1H, br s) 27312 — (300Mhz) 1.57-1.43(10H, m), 1.91-1.85(2H, m), 4.04-3.99(1H, m),7.66(2H, dd), 8.28(1H, d), 8.59(2H, dd), 8.68(1H, d), 9.82(1H, d),12.40(1H, br s) 28 350 — (300Mhz) 2.79(1H, dd), 2.94(1H, dd),3.45-3.32(2H, m), 4.17(1H, d), 4.95(1H, br s), 7.26-7.19(5H, m),7.66(2H, dd), 8.28(1H, d), 8.58(2H, d), 8.68(1H, d), 9.82(1H, d),12.20(1H, br s) 29 348 — (300Mhz) 1.24(9H, s), 7.17(1H, d), 7.30(1H, t),7.53(1H, d), 7.73(2H, d), 7.74(1H, s), 8.38(1H, d), 8.61(2H, d),8.82(1H, d), 12.07(1H, br s), 13.19(1H, br s) 30 272 — (300Mhz) 0.82(3H,t), 1.10(3H, d), 1.52-1.40(2H, m), 3.89-3.83(1H, m), 7.65(2H, d),8.30(1H, d), 8.57(2H, d), 8.65(1H, d), 9.91(1H, d) 31 332 — (300Mhz)1.30-1.25(2H, m), 2.11-2.05(1H, m), 3.05-2.99(1H, m), 7.33-7.17(5H, m),7.67(2H, dd), 8.30(1H, d), 8.59(2H, dd), 8.69(1H, d), 9.91(1H, d),13.01(1H, br s) 32 336 — (300Mhz) 3.44(1H, dd), 3.66(1H, dd), 4.76(1H,dd), 5.63(1H, br s), 7.41-7.22(5H, m), 7.63(2H, d), 8.32(1H, d),8.55(2H, d), 8.62(1H, d), 10.29(1H, s), 12.80(1H, br s) 33 336 —(300Mhz) 3.45(1H, dd), 3.66(1H, dd), 4.76(1H, dd), 5.62(1H, br s),7.41-7.22(5H, m), 7.65(2H, d), 8.30(1H, d), 8.57(2H, d), 8.65(1H, d),10.12(1H, s), 12.80(1H, br s) 34 348 — (300Mhz) 1.20(3H, d),1.84-1.77(2H, m), 2.66-2.61(2H, m), 4.03-3.98(1H, m), 7.30-7.16(5H, m),7.67(2H, dd), 8.29(1H, d), 8.58(2H, dd), 8.70(1H, d), 9.76(1H, d),12.8(1H, br s) 35 348 — (300Mhz) 1.20(3H, d), 1.84-1.77(2H, m),2.66-2.60(2H, m), 4.05-3.96(1H, m), 7.30-7.14(5H, m), 7.68(2H, dd),8.30(1H, d), 8.59(2H, d), 8.71(1H, d), 9.70(1H, d), 13.0(1H, br s) 36270 — (300Mhz) 0.23-0.18(2H, m), 0.48-0.42(2H, m), 1.04-0.95(2H, m),3.19(2H, d), 7.67(2H, dd), 8.28(1H, d), 8.59(2H, dd), 8.70(1H, d),9.79(1H, t), 12.96(1H, br s) 37 310 — (300Mhz) 1.51-1.10(7H, m),1.80-1.74(1H, m), 2.29-2.19(2H, m), 3.81-3.70(1H, m), 7.66(2H, d),8.27(1H, d), 8.59(2H, d), 8.67(1H, d), 9.75(1H, d) 38 400 — (300Mhz)7.43-7.24(7H, m), 7.79-7.71(4H, m), 8.40(1H, d), 8.61(2H, d), 8.80(1H,d), 12.24(1H, s), 13.25(1H, br s) 39 350 — (300Mhz) 1.46(3H, d),3.74(3H, s), 5.10(1H, quint.), 6.91(2H, d), 7.30(2H, d), 7.67(2H, d),8.27(1H, d), 8.59(2H, d), 8.70(1H, d), 10.10(1H, d) 40 327 — (300Mhz)1.52-1.24(6H, m), 2.47-2.40(6H, m), 3.43(2H, t), 7.68(2H, d), 8.30(1H,d), 8.59(2H, dd), 8.70(1H, d), 9.81(1H, t) 41 336 — (300Mhz)3.41-3.34(1H, m), 3.72-3.61(1H, m), 4.72-4.70(1H, dd), 5.63(1H, d),7.41-7.22(5H, m), 7.65(2H, d), 8.30(1H, d), 8.57(2H, d), 8.65(1H, d),10.11(1H, br s) 42 377 7.2 3.04-3.14(4H, m), 3.70-3.79(4H, m), 6.98(2H,d), 7.59(2H, d), 7.71(2H, d), 8.37(1H, d), 8.61(2H, d), 11.91(1H, br s),13.20(1H, br s) 43 374 7.2 1.10-1.90(10H, m), 2.40-2.56(1H, m), 7.22(2H,d), 7.62(2H, d), 7.72(2H, d), 8.39(1H, d), 8.61(2H, d), 8.80(1H, d),12.10(1H, br s) 44 375 8.8 1.48-1.68(6H, m), 3.05-3.15(4H, m), 6.93(2H,d), 7.56(2H, d), 7.72(2H, d), 8.36(1H, d), 8.61(2H, d), 8.80(1H, d),11.90(1H, s), 13.20(1H, br s) 45 336 8.1 1.31(3H, t), 4.01(2H, q),6.94(2H, d), 7.62(2H, d), 7.72(2H, d), 8.39(1H, d), 8.61(2H, d),8.80(1H, d), 11.99, 13.25(1H, 2br s) 46 390 7.1 2.23(3H, s),2.43-2.50(4H, m), 3.08-3.14(4H, m), 6.95(2H, d), 7.59(2H, d), 7.72(2H,d), 8.37(1H, d), 8.61(2H, d), 8.80(1H, d), 11.92(0.5H, s) 47 404 7.11.03(3H, t), 2.38(2H, q), 2.45-2.54(4H, m), 3.06-3.14(4H, m), 6.95(2H,d), 7.58(2H, d), 7.72(2H, d), 8.38(1H, d), 8.61(2H, d), 8.80(1H, d),12.00(0.4H, s) 48 306 6.3 3.39(3H, s), 7.10-7.39(5H, m), 7.46-7.60(2H,m), 7.80-8.02(2H, m), 8.48-8.56(2H, m), 12.10(0.1H, br s) 49 320 6.92.20(3H, s), 3.30(3H, s), 7.00-7.20(4H, m), 7.50-7.62(2H, m),7.85-8.02(2H, m), 8.49-8.60(2H, m), 12.10(0.2H, br s) 50 320 8.81.20(3H, t), 2.61(2H, q), 6.98(1H, br d), 7.25-7.32(1H, m),7.51-7.60(2H, m), 7.72(2H, d), 8.39(1H, d), 8.61(2H, d), 8.81(1H, d),12.02(1H, s), 13.26(0.8H, br s) 51 306 8.3 2.31(3H, s), 6.94(1H, d),7.23-7.29(1H, m), 7.48-7.59(2H, m), 7.72(2H, d), 8.39(1H, d), 8.61(2H,d), 8.81(1H, d), 12.02(0.5H, s) 52 391 6.7 1.40-1.57(2H, m),1.76-1.87(2H, m), 2.75-2.86(2H, m), 3.43-3.68(3H, m), 4.70(1H, d),6.95(2H, d), 7.56(2H, d), 7.73(2H, d), 8.37(1H, d), 8.61(2H, d),8.80(1H, d), 11.90(1H, s), 13.20(0.6H, br s) 53 476 9.1 1.42(9H, s),3.02-3.10(4H, m), 3.41-3.50(4H, m), 6.98(2H, d), 7.60(2H, d), 7.71(2H,d), 8.38(1H, d), 8.61(2H, d), 8.80(1H, d11.93(0.6H, s) 54 376 6.22.81-2.97(4H, m), 3.00-3.12(4H, m), 6.89-6.99(2H, m), 7.52-7.62(2H, m),7.65-7.75(2H, m), 8.38(1H, br s), 8.55-8.62(2H, m), 8.75(1H, br s),12.15(0.6H, br s)

Example 13

N-(6-Oxo-1,6-dihydro-[3,4′]bipyridinyl-5-yl)-benzenesulfonamide-IV-1

Amrinone (100 mg, 0.53 mmol) was suspended in pyridine (2 mL) andbenzenesulfonyl chloride (75 μL, 0.59 mmol) was added dropwise at 0° C.The reaction mixture was stirred for 2 hours. The pyridine was removedin vacuo. MeOH was added to the crude mixture and the solid was filteredand rinsed with more MeOH to give the title compound as a light yellowsolid (100 mg, 57% yield). MS (ES⁺) m/e=328. ¹H NMR (DMSO-d₆) δH 7.51(2H, dd), 7.54-7.58 (2H, m), 7.61-7.65 (1H, m), 7.75 (2H, dd), 7.90 (2H,dd), 8.56 (2H, dd), 9.78 (1H, br s), 12.33 (1H, br s).

Example 14 ITK Inhibition Assay

Compounds were screened for their ability to inhibit Itk using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 0.01% BSA and1 mM DTT. Final substrate concentrations were 15 μM [γ-33P]ATP (400 mCi33P ATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 2 μMpeptide (SAM68 protein D332-443). Assays were carried out at 25° C. inthe presence of 30 nM Itk. An assay stock buffer solution was preparedcontaining all of the reagents listed above, with the exception of ATPand the test compound of interest. 50 μL of the stock solution wasplaced in a 96 well plate followed by addition of 1.5 μL of DMSO stockcontaining serial dilutions of the test compound (typically startingfrom a final concentration of 15 μM with 2-fold serial dilutions) induplicate (final DMSO concentration 1.5%). The plate was pre-incubatedfor 10 minutes at 25° C. and the reaction initiated by addition of 50 μL[γ-33P]ATP (final concentration 15 μM).

The reaction was stopped after 10 minutes by the addition of 50 μL of aTCA/ATP mixture (20% TCA, 0.4 mM ATP). A Unifilter GF/C 96 well plate(Perkin Elmer Life Sciences, Cat no. 6005174) was pretreated with 50 μLMilli Q water prior to the addition of the entire reaction mixture (150μL). The plate was washed with 200 μL Milli Q water followed by 200 mLof a TCA/ATP mixture (5% TCA, 1 mM ATP). This wash cycle was repeated afurther 2 times. After drying, 30 μL Optiphase ‘SuperMix’ liquidscintillation cocktail (Perkin Elmer) was added to the well prior toscintillation counting (1450 Microbeta Liquid Scintillation Counter,Wallac).

IC50 data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

Assays were carried out in a mixture of 20 mM MOPS (pH 7.0), 10 nMMgCl2, 0.1% BSA and 1 mM DTT. Final substrate concentrations in theassay were 7.5 μM [γ-33P]ATP (400 mCi 33P ATP/mmol ATP, AmershamPharmacia Biotech/Sigma Chemicals) and 3 μM peptide (SAM68 proteinD332-443). Assays were carried out at 25° C. in the presence of 50 nMItk. An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of ATP and the test compoundof interest. 50 μL of the stock solution was placed in a 96 well platefollowed by addition of 2 μL of DMSO stock containing serial dilutionsof the test compound (typically starting from a final concentration of50 μM with 2-fold serial dilutions) in duplicate (final DMSOconcentration 2%). The plate was pre-incubated for 10 minutes at 25° C.and the reaction initiated by addition of 50 μL [γ-33P]ATP (finalconcentration 7.5 μM).

The reaction was stopped after 10 minutes by the addition of 100 mL 0.2Mphosphoric acid+0.01% TWEEN 20. A multiscreen phosphocellulose filter96-well plate (Millipore, Cat no. MAPHNOB50) was pretreated with 10 μL0.2M phosphoric acid+0.01% TWEEN 20 prior to the addition of 170 mL ofthe stopped assay mixture. The plate was washed with 4×200 μL 0.2Mphosphoric acid+0.01% TWEEN 20. After drying, 30 μL Optiphase ‘SuperMix’liquid scintillation cocktail (Perkin Elmer) was added to the well priorto scintillation counting (1450 Microbeta Liquid Scintillation Counter,Wallac).

Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

In general, compounds of the invention are effective for the inhibitionof ITK. Preferred compounds showed Ki below 0.1 μM in the radioactiveincorporation assay (I-68, I-71, I-74, I-77, I-81, II-14, II-17, II-20,II-22, II-23, II-28, II-29, II-30, II-31, II-35, II-40, II-46, II-51,II-58, II-63, II-64, II-65, II-66, II-77, II-78, II-79, II-80, II-81,II-97, II-107, II-112, II-114, II-115, II-126, II-129, II-130, II-131,II-134, II-135, II-136, II-138, II-139, II-142, II-143, II-145, II-146,II-147, II-148, II-153, II-155, II-156, II-157, II-158, II-159, II-160,II-162, II-163, II-164, II-165, II-166, II-167, II-168, II-169, II-170,II-171, II-172, II-177, II-178, II-179, II-181, II-182, III-42, III-44,III-46, III-47, III-52, III-54). Preferred compounds showed Ki between0.1 μM and 1 μM in the radioactive incorporation assay (I-5, I-10, I-11,I-20, I-21, I-22, I-27, I-45, I-46, I-47, I-69, I-72, I-73, I-75, I-82,I-83, I-84, I-85, II-4, II-7, II-15, II-21, II-32, II-34, II-38, II-39,II-41, II-43, II-45, II-47, II-52, II-56, II-57, II-59, II-60, II-61,II-62, II-69, II-70, II-71, II-75, II-76, II-83, II-85, II-87, II-95,II-98, II-99, II-100, II-101, II-104, II-105, II-108, II-120, II-121,II-123, II-124, II-132, II-133, II-137, II-140, II-144, II-149, II-150,II-151, II-152, II-154, II-161, II-174, II-175, II-176, III-4, III-5,III-7, III-8, III-11, III-16, III-43, III-45).

Example 15 ITK Inhibition Assay (UV)

Compounds were screened for their ability to inhibit Itk using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249).

Assays were carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mMMgCl2, 0.1% BSA, 1 mM DTT, 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase. Finalsubstrate concentrations in the assay were 100 μM ATP (Sigma Chemicals)and 3 μM peptide (Biotinylated SAM68 D332-443). Assays were carried outat 25° C. and in the presence of 100 nM Itk.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of ATP and the test compoundof interest. 60 μl of the stock solution was placed in a 96 well platefollowed by addition of 2 μl of DMSO stock containing serial dilutionsof the test compound (typically starting from a final concentration of15 μM). The plate was preincubated for 10 minutes at 25° C. and thereaction initiated by addition of 5 μl of ATP. Initial reaction rateswere determined with a Molecular Devices SpectraMax Plus plate readerover a 10 minute time course. IC50 and Ki data were calculated fromnon-linear regression analysis using the Prism software package(GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, SanDiego Calif., USA).

In general, compounds of the invention are effective for the inhibitionof ITK. Preferred compounds showed Ki below 0.1 μM in the coupled enzymeassay (I-70, I-76, I-78, I-79, I-80). Preferred compounds showed Kibetween 0.1 μM and 1 μM in the coupled enzyme assay (I-5, I-10, I-11,I-69, I-82, I-83, I-84, II-4, II-7, II-41).

Example 16 BTK Inhibition Assay

Compounds were screened for their ability to inhibit Btk using aradioactive-phosphate incorporation assay at Vertex Pharmaceuticals.Assays were carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mMMgCl2, 0.1% BSA and 1 mM DTT. Final substrate concentrations in theassay were 50 μM [γ-33P]ATP (200 mCi 33P ATP/mmol ATP, AmershamPharmacia Biotech, Amersham, UK/Sigma Chemicals) and 2 μM peptide (SAM68D332-443). Assays were carried out at 25° C. and in the presence of 25nM Btk. An assay stock buffer solution was prepared containing all ofthe reagents listed above, with the exception of the peptide and thetest compound of interest. 75 μL of the stock solution was placed in a96 well plate followed by addition of 2 μL of DMSO stock containingserial dilutions of the test compound (typically starting from a finalconcentration of 15 μM) in duplicate (final DMSO concentration 2%). Theplate was preincubated for 15 minutes at 25° C. and the reactioninitiated by addition of 25 μL peptide (final concentration 2 μM).Background counts were determined by the addition of 100 mL 0.2Mphosphoric acid+0.01% TWEEN to control wells containing assay stockbuffer and DMSO prior to initiation with peptide.

The reaction was stopped after 10 minutes by the addition of 100 mL 0.2Mphosphoric acid+0.01% TWEEN. A multiscreen phosphocellulose filter96-well plate (Millipore, Cat no. MAPHNOB50) was pretreated with 100 μL0.2M phosphoric acid+0.01% TWEEN 20 prior to the addition of 170 mL ofthe stopped assay mixture. The plate was washed with 4×200 μL 0.2Mphosphoric acid+0.01% TWEEN 20. After drying, 30 μL Optiphase ‘SuperMix’liquid scintillation cocktail (Perkin Elmer) was added to the well priorto scintillation counting (1450 Microbeta Liquid Scintillation Counter,Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis usingthe Prism software package (GraphPad Prism version 3.0cx for Macintosh,GraphPad Software, San Diego Calif., USA).

In general, compounds of the invention, including compounds in Table 1,are effective for the inhibition of Btk. Preferred compounds showed Kiabove 0.5 μM in the radioactive incorporation assay (II-43, II-61,II-114, II-149). Preferred compounds showed Ki below 0.5 μM in theradioactive incorporation assay (II-51, II-58, II-61, II-63, II-77,II-78, II-80, II-112).

Example 17 BTK Inhibition Assay (AlphaScreen™)

Compounds were screened for their ability to inhibit Btk using anAlphaScreen™ phosphotyrosine assay at Vertex Pharmaceuticals. Assayswere carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mM MgCl2, 0.1%BSA and 1 mM DTT. Final substrate concentrations in the assay were 50 μMATP (Sigma Chemicals) and 2 μM peptide (Biotinylated SAM68 D332-443).Assays were carried out at 25° C. and in the presence of 25 nM Btk. Anassay stock buffer solution was prepared containing all of the reagentslisted above, with the exception of peptide and the test compound ofinterest. 37.5 μL of the stock solution was placed in each well of a 96well plate followed by 1 μL of DMSO containing serial dilutions of thetest compound (typically starting from a final concentration of 15 μM)in duplicate (final DMSO concentration 2%). The plate was preincubatedfor 15 minutes at 25° C. and the reaction initiated by addition of 12.5μL peptide (final concentration 2 μM). Background counts were determinedby the addition of 5 μL 500 mM EDTA to control wells containing assaystock buffer and DMSO prior to initiation with Biotin-SAM68.

The reaction was stopped after 30 minutes by diluting the reaction225-fold into MOPS buffer (20 mM MOPS (pH 7.0), 1 mM DTT, 10 mM MgCl2,0.1% BSA) containing 50 mM EDTA to bring the final concentration ofpeptide to 9 nM.

AlphaScreen™ reagents were prepared according to the manufacturersinstructions (AlphaScreen™ phosphotyrosine (P-Tyr-100) assay kit,PerkinElmer catalogue number 6760620C). Under subdued lighting, 20 μL ofAlphaScreen™ reagents were placed in each well of a white half area 96well plate (Corning Inc.—COSTAR 3693) with 30 μL of the stopped, dilutedkinase reactions. Plates were incubated in the dark for 60 minutes priorto reading on a Fusion Alpha plate reader (PerkinElmer).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis usingthe Prism software package (GraphPad Prism version 3.0cx for Macintosh,GraphPad Software, San Diego Calif., USA).

Example 18 RLK Inhibition Assay

Compounds were screened for their ability to inhibit Rlk using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 20 mM MOPS (pH 7.0), 10mM MgCl2, 0.1% BSA and 1 mM DTT. Final substrate concentrations in theassay were 100 μM ATP (Sigma Chemicals) and 10 μM peptide (Poly Glu:Tyr4:1). Assays were carried out at 30° C. and in the presence of 40 nMRlk. Final concentrations of the components of the coupled enzyme systemwere 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/ml pyruvate kinaseand 10 μg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of ATP and the test compoundof interest. 60 μl of the stock solution was placed in a 96 well platefollowed by addition of 2 μl of DMSO stock containing serial dilutionsof the test compound (typically starting from a final concentration of7.5 μM). The plate was preincubated for 10 minutes at 30° C. and thereaction initiated by addition of 5 μl of ATP. Initial reaction rateswere determined with a Molecular Devices SpectraMax Plus plate readerover a 10 minute time course. IC50 and Ki data were calculated fromnon-linear regression analysis using the Prism software package(GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, SanDiego Calif., USA).

In general, compounds of the invention are effective for the inhibitionof RLK. Preferred compounds showed Ki above 1 μM in the coupled enzymeassay (I-5, I-11, I-71, I-74, II-7, II-15, II-17, II-38, II-41, II-46,II-47, II-65, II-75, II-83, II-85, II-87, II-114, II-115, II-143,II-148, II-149, II-159, II-160, II-163, II-164, II-166, II-168, II-171,II-178, II-179, III-4, III-5). Preferred compounds showed Ki below 1 μMin the coupled enzyme assay (II-14, II-28, II-29, II-30, II-31, II-35,II-40, II-77, II-78, II-79, II-80, II-81, II-112).

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1. A compound of formula I:

or a pharmaceutically accepted salt thereof, wherein each R³ and R⁴ is independently H, halogen or C₁₋₄ aliphatic optionally substituted with halogen, C₁₋₂aliphatic, OCH₃, NO, NH₂, CN, NHCH₃, SCH₃, or N(CH)₂. R² is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, R² is optionally substituted with J^(R); each X¹ and X² is independently —C(O)—, —NR—, or —SO₂— wherein one of X¹ or X² is —NR— and the other of X¹ or X² is —C(O)— or —SO₂—; R is H, unsubstituted Coo aliphatic; R¹ is -T-Q; T is a bond or C₁₋₆ aliphatic, wherein up to three methylene units of the chain are optionally and independently replaced by G or G′ wherein G is —NR⁵—, —O—, —S—, —SO—, SO₂—, —CS—, or —CO—; G′ is cyclopropyl, C≡C, or C═C; T is optionally substituted with J^(T); Q is independently hydrogen, a C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q is optionally substituted with J^(Q); R⁵ is optionally substituted R, C₆₋₁₀ aryl, C₃₋₁₀ (cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl; or two R⁵ groups, together with the atom(s) to which they are attached, form an optionally substituted 3-7 membered monocyclic or 8-14 membered bicyclic ring; J^(R), J^(T), and J^(Q) substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halogen; —R^(o); C₁₋₆alkyl, optionally substituted with R^(o), wherein up to three methylene units of the chain are optionally and independently replaced by, —NR—, —O—, —S—, —SO—, SO₂—, —CO—, cyclopropyl, C≡C, or C═C in a chemically stable arrangement; —OCF₃; —SCF₂; C₁₋₄haloalkyl; —CH₂-halogen; C₆₋₁₀aryl, optionally substituted with R^(o); 5-12 membered heteroaryl optionally substituted with R^(o); 3-12 membered heterocyclic ring optionally substituted with R^(o); —O(Ph) optionally substituted with R^(o); —CH═CH(Ph), optionally substituted with R^(o); —CH≡CH(Ph), optionally substituted with R^(o); —C₁₋₆alkyl-(3-12 membered heterocyclyl), optionally substituted with R^(o); —C₁₋₆alkyl-(C₆₋₁₀aryl), optionally substituted with R^(o); —C₁₋₆alkyl-(5-10 membered heteroaryl), optionally substituted with R^(o); C₃₋₁₀cycloaliphatic, optionally substituted with R^(o); —C₁₋₆alkyl-(C₃₋₁₀cycloaliphatic), optionally substituted with R^(o); —(C₁₋₆alkyl)-OR^(o), optionally substituted with R^(o); —(C₁₋₆alkyl)-N(R^(o))₂, optionally substituted with R^(o); —(C₁₋₆alkyl)-SR^(o), optionally substituted with R^(o); —NO₂; —CN; —OR^(o); —SR^(o); —N(R)₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂; —NR^(o)C(S)(R^(o))N(R^(o))₂; —NR^(o)COR^(o); —NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o) NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂; —OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o); —C(NOR^(o))R^(o); —S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o); —NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o); —C(═NH)—N(R^(o))₂; —P(O)R^(o); —PO(R^(o))₂; —OPO(R^(o))₂; and —(CH₂)₀₋₂NHC(O)R^(o); each R^(o) is independently selected from hydrogen, NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), haloC₁₋₄aliphatic, optionally substituted C₁₋₆ aliphatic wherein up to 2 methylene units are optionally replaced by O, N, or S, optionally substituted 5-8 membered heterocyclyl, unsubstituted 56 membered heteroaryl, unsubstituted 3-6 membered cycloaliphatic, unsubstituted phenyl, unsubstituted —O(Ph), unsubstituted —CH₂(Ph), unsubstituted —CH₂(5-7 membered heterocyclyl), or unsubstituted —CH₂(5-6 membered heteroaryl); or, notwithstanding the definition above, two independent occurrences of R^(o), on the same substituent or different substituents, taken together with the atom(s) to which each R^(o) group is bound, form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; optional substituents on the aliphatic group of R^(o) or on the ring formed by 2 R^(o) groups are selected from NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), and haloC₁₋₄aliphatic, wherein each of the foregoing C₁₋₄aliphatic groups of R^(o) is unsubstituted; J^(R), J^(T), and J^(Q) substituents on the saturated carbon of an aliphatic group, a heteroaliphatic group, or a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), ═NOH, and ═NR*, where each R* is independently selected from hydrogen or an optionally substituted C₁₋₆ aliphatic group; J^(R), J^(T), and J^(Q) substituents on the nitrogen of a non-aromatic heterocyclic ring or on the nitrogen of the heteroaryl ring are selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺¹)₂, —C(═NH)N(R⁺)₂, and —NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆ aliphatic, optionally substituted phenyl, optionally substituted —O(Ph), optionally substituted —CH₂(Ph), optionally substituted —(CH₂)₂(Ph); optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R⁺, on the same substituent or different substituents, taken together with the atom(s) to which each R⁺ group is bound, form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; optional substituents on the aliphatic group or the phenyl ring of R⁺ are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), and halo(C₁₋₄ aliphatic), wherein each of the foregoing C₁₋₄aliphatic groups of R⁺ is unsubstituted; provided that when R² is 4-pyridyl or 3-pyridyl, R³ is H, X's —NR—, R is H, and X² is —C(O)—; then a) R¹ is not CH(CH₃)OC(═O)CH₃; CH₂OC(═O)CH₃; or CH₂C(═O)CH₃; b) R¹ is not C₁₋₆alkyl or O(C₁₋₆alkyl); when R² is 4-pyridyl, R³ and R⁴ are H, X¹ is —NR—, R is H, and X² is —C(O)—, then a) when T is a bond, Q is not methyl, imidazole, OCH₃, or H; b) when T is —CH₂—, Q is not 3-OH-phenyl, 4-OH-phenyl, 4-pyridyl, 3-NO₂-phenyl, OH, —O(C═O)CH₃, or —C(═O)CH₃; c) when T is —CH(CH₃)—, Q is not —OC(═O)CH₃; d) when T is —CH₂CH₂—, Q is not 2-pyridyl or —COOH; e) when T is CH(CH₃)OC(═O)—, Q is not CH₃; when R² is 4-pyridyl, R³ is H, R⁴ is not H, X¹ is —NR—, R is H, and X² is —C(O)—, then a) when T is a bond, Q is not CH₃; b) R¹ is not CH(CH₃)OC(═O)CH₃; when R² is 2,4-pyrimidyl, R³ and R⁴ are H, X¹ is —NR—, R is H, and X² is —C(O)—, then a) R¹ is not methyl, NHCH₃, or —NHC(═)NH₂; when R² is 4-pyridyl, R³ and R⁴ are H, X¹ is —NR—, R is H, and X² is —SO₂—, then a) when T is a bond, Q is not optionally substituted C₆₋₁₀ aryl or C₅₋₁₀ heteroaryl; when R² is 4-thiazolyl, R³ is H, R⁴ is CH₃, X¹ is —C(O), X² is —NR—, R is H, then a) when T is —CH₂CH₂—, Q is not N(CH₃)₂; when R¹ is unsubstituted phenyl, R³ and R⁴ are H, X¹ is —NR—, R is H, and X² is —C(O)—, then, when T is C₁aliphatic wherein 1 methylene unit of the chain is replaced by G; G is —NR⁵—; and R⁵ is H; then Q is not 2,6-di-isopropylphenyl; when R² is unsubstituted phenyl, R³ is H, R⁴ is CH₃, X¹ is —C(O)—, X² is —NR—, R is H, then a) when T is a bond, Q is not CH₃ or CH₂CH₃; b) when T is —CH₂CH₂—, Q is not unsubstituted phenyl or N(CH₂CH₃)₂; c) when T is —CH₂CH₂CH₂—, Q is not N(C H₂CH₃)₂; d) R¹ is not NH₂; when R² is unsubstituted phenyl, R³ is H, R⁴ is CH₃, X¹ is —NR—, R is H, X² is —C(O)—, then a) when T is —O—CH₂—, Q is not unsubstituted phenyl; when R² is 4-OCH₃ phenyl, R³ is H, R⁴ is CH₃, X¹ is —NR—, R is H, X² is —C(O)—, then a) when T is a bond, Q is not CH₃; when R² is a 6-membered heteroaryl with 2 nitrogens; R³ is H, methyl, or ethyl; R⁴ is methyl or ethyl; X¹ is —NR—, R is H, X² is —C(O)—, then a) R¹ is not CH₃; when X¹ is —C(O)—, X² is —NR—, and R is H, then R¹ is not H or methyl; when R² is

R³ and R⁴ are H, X is —NR—, R is H, and X² is —(O)—, then R¹ is not CH₃; when R² is unsubstituted phenyl, R³ and R⁴ are H, X¹ is —C(O)—, X² is —NR—, R is H, then R¹ is

not
 2. The compound according to claim 1, wherein T is C₁₋₃aliphatic optionally interrupted with zero or one G groups wherein G is selected from O, NR⁵, and S.
 3. The compound according to claim 1, wherein T is —C₁₋₂aliphatic-G- wherein G is O or NR⁵, and G is bound to Q in a chemically stable arrangement.
 4. The compound according to claim 1, wherein T is C₁₋₃aliphatic optionally interrupted with zero G groups.
 5. The compound according to claim 1, wherein T is C₁₋₃aliphatic optionally interrupted with zero or one G′ groups.
 6. The compound according to claim 1, wherein T is —CH₂—.
 7. The compound according to claim 1, wherein T is a bond.
 8. (canceled)
 9. The compound according to claim 1, wherein R³ and R⁴ are both H.
 10. The compound according to claim 9, wherein R² is 5-8 membered monocyclyl optionally substituted with up to five J^(R) groups.
 11. The compound according to claim 10, wherein R² is C₃₋₈cycloaliphatic optionally substituted with up to five J^(R) groups.
 12. The compound according to claim 11 wherein R² is C₃₋₈cycloalkyl optionally substituted with up to five J^(R) groups.
 13. The compound according to claim 11 wherein R² is C₃₋₈cycloalkenyl optionally substituted with up to five J^(R) groups.
 14. The compound according to claim 11, wherein R² is cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, or cycloheptenyl, optionally substituted with up to five J^(R) groups.
 15. The compound according to claim 10, wherein R² is a 5-6 membered aryl or heteroaryl optionally substituted with up to five J^(R) groups.
 16. The compound according to claim 15 wherein R² is a 5-6 membered heteroaryl optionally substituted with up to five J^(R) groups.
 17. The compound according to claim 16, wherein R² is a 6 membered heteroaryl having 1 or 2 nitrogen atoms; R² is optionally substituted with up to five J^(R) groups.
 18. The compound according to claim 17, wherein R² is a pyridine ring optionally substituted with up to five J^(R) groups.
 19. The compound according to claim 18 wherein R² is 2-pyridinyl optionally substituted with up to five J^(R) groups.
 20. The compound according to claim 18 wherein R² is 3-pyridinyl optionally substituted with up to five J^(R) groups.
 21. The compound according to claim 18 wherein R² is 4-pyridinyl optionally substituted with up to five J^(R) groups.
 22. The compound according to claim 17, wherein R² is a pyrimidine ring optionally substituted with up to five J^(R) groups.
 23. The compound according to claim 22 wherein R² is a 2-4 pyrimidinyl optionally substituted with up to five J^(R) groups.
 24. The compound according to claim 16, wherein R² is a 5-membered heteroaryl ring optionally substituted with up to five J^(R) groups.
 25. The compound according to claim 24 wherein R² is a thiophene ring optionally substituted with up to five J^(R) groups.
 26. The compound according to claim 24 wherein R² is a pyrazole ring optionally substituted with up to five J^(R) groups.
 27. The compound according to claim 15, wherein R² is phenyl optionally substituted with up to five J^(R) groups.
 28. The compound according to claim 11, wherein each J^(R) is selected from oxo or ═NOH.
 29. The compound according to claim 15, wherein each J^(R) is selected from C₁₋₆alkyl, C₆₋₁₀aryl, —C₁₋₆alkyl-C₆₋₁₀aryl, C₁₋₄haloalkyl, —OR^(o), —N(R^(o)), —SR^(o), NO₂, CN, 3-12 membered heterocyclyl, —(C₁alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), —CON(R^(o))₂, —SO₂R^(o), —SO₂N(R)₂, or C₁₋₆alkyl wherein up to three methylene units of the chain are independently replaced by, —NR^(o)—, —O—, —S—, —SO—, SO₂—, or —CO— in a chemically stable arrangement; each J^(R) is independently and optionally substituted with It.
 30. The compound according to claim 29, wherein each J^(R) is independently and optionally substituted with R^(o) and is selected from —OR^(o), —N(R^(o))₂, —SR^(o), —(C₁₋₆alkyl)-OR^(o), —(C₁₋₆-alkyl)-N(R^(o))₂, or —(C₁₋₆alkyl)SR^(o).
 31. The compound according to claim 29, wherein each J^(R) is independently selected from optionally substituted 5-8 membered heterocyclyl, optionally substituted —NR(C₁₋₄alkyl)N(R^(o))₂, optionally substituted —NR(C₁₋₄alkyl)OR^(o), —N(R^(o))₂, or optionally substituted —NH(5-6 membered heterocyclyl).
 32. The compound according to claim 31, wherein each J^(R) is independently selected from optionally substituted —NH(5-6 membered heterocyclyl).
 33. The compound according to claim 32, wherein the 5-6 membered heterocyclyl contains 1-2 nitrogen atoms.
 34. The compound according to claim 33 wherein the 5-6 membered heterocyclyl is selected from pyrrolidine, piperidine, or piperazine.
 35. (canceled)
 36. The compound according to claim 35, wherein X¹ is C(O) and X₂ is NR.
 37. The compound according to claim 35, wherein X¹ is NR and X₂ is C(O).
 38. The compound according to claim 36 or claim 37, wherein Q a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
 39. The compound according to claim 38, wherein Q is C₆₋₁₀ aryl, C₃₋₁₀ cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl.
 40. The compound according to claim 39, wherein Q is C₆₋₁₀ aryl or 5-14 membered heteroaryl.
 41. The compound according to claim 40, wherein Q is a 5-6 membered aryl or heteroaryl.
 42. The compound according to claim 41, wherein Q is phenyl.
 43. The compound according to claim 38, wherein Q is substituted with up to 3 J^(Q) groups wherein each J^(Q) is selected from CN, C₁₋₆alkyl, C₁₋₄haloalkyl, —OR^(o), —N(R^(o))₂, —SR^(o), —(C₁₋₆alkyl)-OR^(o), —(C₁₋₆alkyl)-N(R^(o))₂, —(C₁₋₆alkyl)-SR^(o), C₆₋₁₀aryl, —C₁₋₆-alkyl-C₆₋₁₀aryl, C₃₋₁₀cycloaliphatic, —C₁₋₆alkyl-(C₃₋₁₀cycloaliphatic), C₃₋₁₀heterocyclyl, —C₁₋₆alkyl-(C₃₋₁₀heterocyclyl), —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), —CON(R^(o))₂, —SO₂R^(o), —SO₂N(R)₂, or C₁₋₆alkyl wherein up to three methylene units are optionally and independently replaced by, —NR^(o)—, —O—, —S—, —SO—, SO₂—, —CO—, cyclopropyl, C≡C, or C═C in a chemically stable arrangement; each J^(Q) is optionally and independently substituted with R^(o).
 44. The compound according to claim 43, wherein each J^(Q) is —SO₂N(R^(o))₂, —SO₂R^(o), —NR^(o)C(O)OR^(o), —C≡C—R^(o), —C═C—R^(o), phenyl, —O—Ph, —O—CH₂Ph, C₅₋₆heteroaryl, C₃₋₇heterocyclyl, or C₃₋₇cyclyoaliphatic.
 45. The compound according to claim 43, wherein each J^(Q) is CN, C₁₋₆alkyl, —CF₃, —OCF₃, —OR^(o), —N(R^(o))₂, —SR^(o), —CH₂-halogen, —SCF₂, —(C₁₋₆alkyl)-N(R)₂, C₆aryl, C₅₋₆heteroaryl, —C(O)OR^(o), —NR^(o)COR^(o), —COR^(o), or —CON(R^(o))₂.
 46. The compound according to claim 43, wherein R^(o) is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, OH, halogen, —CH₂-pyrrolidine, COCH₃, —(C₁₋₄alkyl)₀₋₁-O(C₁₋₄alkyl), —(C₁₋₄alkyl)₀₋₁-O(C₁₋₄alkyl)OH, —(C₁₋₄alkyl)₀₋₁-NH(C₁₋₄alkyl), —(C₁₋₄alkyl)O—, —N(C₁₋₄alkyl)₂, or —(C₁₋₄alkyl)₀₋₁-NH₂.
 47. The compound of claim 1, where the compound is selected from the following:


48. The compound according to claim 1, wherein the compound is selected from the following:


49. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
 50. A method of inhibiting Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity in: (a) a patient; or (b) a biological sample; which method comprises administering to said patient, or contacting said biological sample with a compound of claim
 1. 51. The method of claim 50, wherein the method comprises inhibiting Itk kinase activity.
 52. A method of treating or lessening the severity of a disease or condition selected from an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease comprising administering to a patient in need thereof a compound according to claim
 1. 53. The method of claim 52, wherein the disease or disorder is asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease Sjogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, greata vernal conjunctivitis, Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies, multiple sclerosis, artherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following, angioplasty, tumours, artherosclerosis, systemic lupus erythematosus, allograft rejection including, without limitation, acute and chronic allograft rejection following for example transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
 54. A compound of formula 22:

wherein: R¹⁰ is an amino protective group; R¹¹ is H or Clue alkyl or R¹⁰ and R¹¹ together with the nitrogen atom to which they are bound form an amine protective group; R¹² is a hydroxyl protecting group; and R², J^(R), and R^(o) are as defined according to claim
 1. 55. A process for preparing a compound of formula I, comprising reacting a compound of formula 22 with a corn mound R²—X, wherein X is an appropriate leaving group to provide a compound of formula 23:

wherein: R¹⁰ is an amino protective group; R¹¹ is H or C₁₋₆ alkyl or R¹⁰ and R¹¹ together with the nitrogen atom to which they are bound form an amine protective group; R¹² is a hydroxyl protecting group; and R², J^(R), and R^(o) are as defined according to claim
 1. 